Ware's art reflects early 20th century American styles of cartooning and graphic design, shifting through formats from traditional comic panels to faux advertisements to cut-out toys. Stylistic influences apparent in his work include advertising graphics from that same era; newspaper strip cartoonists Winsor McCay (Little Nemo in Slumberland) and Frank King (Gasoline Alley); Charles Schulz's post-WWII strip Peanuts, and the cover designs of ragtime-era sheet music. Ware has spoken about finding inspiration in the work of artist Joseph Cornell Pantheon Graphic Novels and cites Richard McGuire's strip Here as a major influence on his use of non-linear narratives.

Ware has said of his own style:

I arrived at my way of "working" as a way of visually approximating what I feel the tone of fiction to be in prose versus the tone one might use to write biography; I would never do a biographical story using the deliberately synthetic way of cartooning I use to write fiction. I try to use the rules of typography to govern the way that I "draw", which keeps me at a sensible distance from the story as well as being a visual analog to the way we remember and conceptualize the world. I figured out this way of working by learning from and looking at artists I admired and whom I thought came closest to getting at what seemed to me to be the "essence" of comics, which is fundamentally the weird process of reading pictures, not just looking at them. I see the black outlines of cartoons as visual approximations of the way we remember general ideas, and I try to use naturalistic color underneath them to simultaneously suggest a perceptual experience, which I think is more or less the way we actually experience the world as adults; we don't really "see" anymore after a certain age, we spend our time naming and categorizing and identifying and figuring how everything all fits together. Unfortunately, as a result, I guess sometimes readers get a chilled or antiseptic sensation from it, which is certainly not intentional, and is something I admit as a failure, but is also something I can't completely change at the moment.

Although his precise, geometrical layouts may appear to some to be computer-generated, Ware works almost exclusively with manual drawing tools such as paper and ink, rulers and T-squares. He does, however, sometimes use photocopies and transparencies, and employs a computer to color his strips.

Ware's earliest published strips appeared in the late 1980s on the comics page of The Daily Texan, the student newspaper of the University of Texas at Austin. In addition to numerous daily strips under different titles, Ware also had a weekly satirical science fiction serial in the paper titled Floyd Farland: Citizen of the Future. This was eventually published in 1988 as a prestige format comic book from Eclipse Publishing, and its publication even led to a brief correspondence between Ware and Timothy Leary. Now embarrassed by the book, which he considers amateurish and naive, Ware is reportedly purchasing and destroying all remaining copies.

While still a sophomore at UT, Ware came to the attention of Art Spiegelman, who invited Ware to contribute to RAW, the influential anthology magazine Spiegelman was co-editing with Françoise Mouly. Ware has acknowledged that being included in the prestigious RAW gave him confidence and inspired him to explore printing techniques and self-publishing. His Fantagraphics series Acme Novelty Library defied comics publishing conventions with every issue. The series featured a combination of new material as well as reprints of work Ware had done for the Texan (such as Quimby the Mouse) and the Chicago weekly paper Newcity. Ware's work appeared originally in Newcity before he moved on to his current "home", the Chicago Reader. Beginning with the 16th issue of the Acme Novelty Library, Ware is self-publishing his work, while maintaining a relationship with Fantagraphics for distribution and storage. This is an interesting return to Ware's early career, when he self-published such books as Lonely Comics and Stories as well as miniature digests of stories based on Quimby the Mouse and an unnamed potato-like creature.

In recent years he has also been involved in editing (and designing) several books and book series, including the new reprint series of Gasoline Alley from Drawn and Quarterly Walt and Skeezix, the on-going reprint of Krazy Kat by Fantagraphics, and the thirteenth volume of Timothy McSweeney's Quarterly Concern, which is devoted to comics. He was the editor of The Best American Comics 2007, the 2nd installment devoted to comics in the Best American series.

In 2007 Ware curated an exhibition for the Phoenix Art Museum focused on the non-comic work of five contemporary cartoonists. The exhibition, titled "UnInked: Paintings, Sculpture and Graphic Works by Five Cartoonists," ran from April 21 through August 19. Ware also edited and designed the catalog for the exhibition.

Quimby the Mouse

Quimby the Mouse was an early character for Ware and something of a breakthrough. Rendered in the style of an early animation character like Felix the Cat, Quimby the Mouse is perhaps Ware's most autobiographical character. Quimby's relationship with a cat head named Sparky is by turns conflict-ridden and loving, and thus intended to reflect all human relationships. While Quimby exhibits mobility, Sparky remains immobile and helpless, subject to all the indignities Quimby visits upon him. Quimby also acts as a narrator for Ware's reminiscences of his youth, in particular his relationship with his grandmother. Quimby was presented in a series of smaller panels than most comics, almost providing the illusion of motion ala a zoetrope. In fact, Ware once designed a zoetrope to be cut out and constructed by the reader in order to watch a Quimby "silent movie". Ware's ingenuity is neatly shown in this willingness to break from the confines of the page. Quimby the Mouse appears in the logo of a Chicago-based bookstore " Quimby's", although their shared name was originally a coincidence :: Quimby's ::

Rusty Brown

Ware is currently at work on Rusty Brown, a series ostensibly about an action figure collecting manchild and his somewhat troubled childhood, but which, in Ware's fashion, diverges into multiple storylines about Brown's father's early life in the 1950s as a science fiction writer (Acme Novelty Library #19) and his best friend Chalky White's adult home life.

Building Stories

Ware is currently working on "Building Stories", which first appeared as a monthly strip in Nest Magazine. Installments have since appeared in a number of publications, including The New Yorker, Kramer's Ergot, and most notably, the Sunday New York Times Magazine. "Building Stories" appeared weekly in the New York Times Magazine from September 18, 2005 until April 16, 2006. A full chapter was published in Acme Novelty Library Number 18.

The Super-Man

The Super-Man is an antihero who wears a similar caped costume to Superman, but also has a domino mask and receding hairline. Ware has said in interviews that he imagines that if the popular fictional superhero Superman were real, he would be much like Ware's Super-Man.

The Super-Man originally appeared as God in Ware's early work, wreaking vengeance on people who annoyed him. The Super-Man later turned up in Ware's Jimmy Corrigan, the Smartest Kid on Earth. In one scene, Jimmy sees the Super-Man standing on the cornice of a skyscraper. Seeing Jimmy, he waves, to Jimmy's delight. The Super-Man then crouches as if to take off flying, but instead falls to his death.

In a series of strips appearing in the Chicago Reader, the Super-Man is seen walking about naked, eating a live deer, stealing money, killing people who annoy him, gambling, and kidnapping a young girl and living with her in the wild until she grows up, whereupon he impregnates her, grows bored with her and the child, then flies off. He then spends the next several million years in one spot, pondering it all even as the Earth falls away about him. His last thought remains of the girl and his child.

These strips have been compiled and published in 2005 as part of a book titled The ACME Novelty Library Final Report to Shareholders and Saturday Afternoon Rainy Day Fun Book. However they are not listed in the table of contents.

Ware is an ardent collector of ragtime paraphernalia and occasionally publishes a journal devoted to the music titled The Ragtime Ephemeralist. He also plays the banjo and piano. The influence of the music and the graphics of its era can be seen in Ware's work, especially in regard to logos and layout. Ware has designed album covers and posters for such ragtime performers as the Et Cetera String Band, Virginia Tichenor, Reginald R. Robinson, the Paragon Ragtime Orchestra, and Guido Nielsen.

He has also designed covers and posters for non-ragtime performers such as Andrew Bird's Bowl of Fire and 5ive Style. [1] Ware also designed the façade of the San Francisco writing lab and pirate store 826 Valencia. In October 2005 Ware designed the elaborate cover art for Penguin Books' new edition of Voltaire's Candide.

In 2003-2004, Ware worked with Ira Glass of This American Life and Chicago historian Tim Samuelson to illustrate and design Lost Buildings about Samuelson and the preservation of Chicago's old buildings, particularly Louis Sullivan's buildings. Originally produced for a live "Lost in America" stage show in 2003, Lost Buildings was later published as a book and DVD. In 2007-2008 he produced animations for the This American Life television series on Showtime and also contributed to the show as a color consultant. Ware created the poster art for the 2007 film The Savages.

Fortune 500 cover

In 2010, Ware designed the cover for Fortune magazine's "Fortune 500" issue, but it was rejected ComicsBeat.com. Ware had mentioned the work at a panel at the Chicago Comic and Entertainment Expo on April 16, as first noted in an April 20 blog post by Matthew J. Brady. The cover, featuring the circle-shaped humans common in Ware's more broadly socially satirical comic-strips, turned the numbers 500 into skyscrapers looming over the continental United States. On the roofs, corporate bosses drink, dance, and sun themselves as a helicopter drops a shovelful of money down for them. Below, among signs reading "Credit Default Swap Flea Market," "Greenspan Lube Pro," and "401K Cemetery," a helicopter scoops money out of the US Treasury with a shovel, cars pile up in Detroit, and flag-waving citizens party around a boiling tea kettle in the shape of an elephant. In the Gulf of Mexico, homes are sinking, while hooded prisoners sit in Guantanamo, a "Factory of Exploitation" keeps going in Mexico, China is tossing American dollars into the Pacific, and the roof of bankrupted Greece's Treasury has blown off. A spokesperson for the magazine only said that, as is their practice, they had commissioned a number of possible covers from different artists, including Ware. Brady wrote in his blog that Ware said at the panel he "accepted the job because it would be like doing the [cover for the 1929 issue of the magazine".

Over the years his work garnered several awards, including the 1999 National Cartoonists Society Award for Best Comic Book for Acme Novelty Library.

In addition, Acme Novelty Library won the 1996 and 2000 Eisner Awards for Best Continuing Series, as well as the 2000 Eisner for Best New Graphic Album. Jimmy Corrigan, the Smartest Kid on Earth won the 2001 Eisner for Best Reprint Graphic Album. In 2008, Ware won the Best Writer/Artist: Drama Eisner for Acme Novelty Library 18. Ware has won the Best Colorist Eisner four times, in 1996, 1998, 2001, and 2006. His publication design has been awarded the Eisner six times, in 1995—1997, 2001—2002, and 2006.

Ware has won the Harvey Award for Best Letterer four times, in 1996, 2000, 2002, and 2006. He has won the Best Colorist Harvey Award in 1996—1998, 2000, 2002, and 2004. He also won the Best Cover Artist Harvey Award in 2000. Ware won the Harvey Award for Excellence in Production/Presentation five consecutive years, from 1995—2000. In addition, Acme Novelty Library won the Best Continuing Series Harvey Award in 1995, and the Best Continuing or Limited Series in 1995—1996. Acme Novelty Library also won the Best Single Issue or Story Harvey Award in 1997 and 2000. The Jimmy Corrigan book won the 2001 Harvey Award for Best Graphic Album of Previously Published Work. In 2006, Ware was awarded the Harvey for Best Cartoonist.

In 2002, Ware became the first comics artist to be invited to exhibit at Whitney Museum of American Art biennial exhibition. With Will Eisner, Jack Kirby, Harvey Kurtzman, Robert Crumb and Gary Panter, Ware was among the artists honored in the exhibition "Masters of American Comics" at the Jewish Museum in New York City, New York, from September 16, 2006 to January 28, 2007. His work was the subject of solo exhibitions at the Museum of Contemporary Art, Chicago in 2006 and at the University of Nebraska's Sheldon Museum of Art, in 2007.

Ware's graphic novel Jimmy Corrigan, the Smartest Kid on Earth won the 2001 Guardian First Book Award, the first time a graphic novel has won a major United Kingdom book award. It also won the prize for best album at the 2003 Angoulême International Comics Festival in France.

In 2006, Ware received a USA Hoi Fellow grant from United States Artists. USA Fellows 2006 Visual Arts: Chris Ware, United States Artists