An investigator starts research in a new field with faith, a foggy idea, and a few wild experiments. Eventually the interplay of negative and positive results guides the work. By the time the research is completed, he or she knows how it should have been started and conducted. 
Cram attended the Winwood High School in Long Island, N.Y. From 1938 to 1941, he attended Rollins College, in Winter Park, Florida on a national honorary scholarship, where he worked as an assistant in the chemistry department, and was active in theater, chapel choir, Lambda Chi Alpha, Phi Society, and Zeta Alpha Epsilon. It was at Rollins that he became known for building his own chemistry equipment. In 1941, he graduated from Rollins College with a B.S. in Chemistry.
Cram once admitted that his career wasn't without sacrifice. His first wife was Rollins classmate, Jean Turner, who also graduated in 1941, and went on to receive a master's degree in social work from Columbia University. His second wife, Jane, is a former chemistry professor at Mt. Holyoke College. Cram chose not to have any children, "because I would either be a bad Father or a bad scientist."
From 1942-1945, 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.
Cram was named an assistant professor at the University of California, Los Angeles in 1947, and a professor in 1955. He served there until his retirement in 1987. He was a popular Teacher, having instructed some 8,000 undergraduates in his career and guided the academic output of 200 graduate students. He entertained his classes by strumming his guitar and singing folk songs. He showed a self-deprecating style, saying at one time: