Klinghoffer has published a series of articles, editorial columns, and letters to the editor in both Jewish and conservative publications seeking to promote opposition to Darwinian views of evolution. Larry Yudelson has responded, in a piece directed at Klinghoffer, that rabbinical Judaism has accepted evolutionary theory for more than a century, and that Judaism has never rejected science. Yudelson also charges that Klinghoffer is paid to promote his ideas by his employer, the Discovery Institute, which Yudelson identifies as a Christian think tank that is funded by organizations that seek to promote a "Christian-friendly world view."

Klinghoffer is a practicing Orthodox Jew who has written a spiritual memoir about his journey from Reform Judaism to becoming ba'al tshuva (Hebrew, a newly religious Orthodox Jew).In his book Why the Jews Rejected Jesus, Klinghoffer theorizes that Jewish rejection of Jesus allowed Christianity to separate from Judaism and become a multi-ethnic religion. Christianity was thus able to achieve a dominance in gentile Europe that would have been impossible for Judaism to attain. To Klinghoffer, this changed world history, because Christianity was able to serve as a bulwark against the spread of Islam into Europe.

In May 2010, the Discovery Institute released a free 105 page eBook titled Signature of Controversy: Responses to Critics of Signature in the Cell edited by Klinghoffer with chapters by Discovery Institute fellows David Berlinski, Casey Luskin, Stephen C. Meyer, Paul Nelson, Jay Richards and Richard Sternberg.