From 1942 to 1945, Cram worked in chemical research at Merck & Co laboratories, doing penicillin research with mentor Max Tishler. Postdoctoral work was as an American Chemical Society postdoctoral fellow at the Massachusetts Institute of Technology, with John D. Roberts. Cram was the originator of Cram's rule, which provides a model for predicting the outcome of nucleophilic attack of carbonyl compounds. He published over 350 research papers and eight books on organic chemistry, and taught graduate and post-doctoral students from 21 different countries.