Cram expanded upon Charles Pedersens ground-breaking synthesis of crown ethers, two-dimensional organic compounds that are able to recognize and selectively combine with the ions of certain metal elements. He synthesized molecules that took this chemistry into three dimensions, creating an array of differently shaped molecules that could interact selectively with other chemicals because of their complementary three-dimensional structures. Crams work represented a large step toward the synthesis of functional laboratory-made mimics of enzymes and other natural molecules whose special chemical behavior is due to their characteristic structure. He also did work in stereochemistry and Cram's rule of asymmetric induction is named after him.
In 1973, Cram collaborated on research with Irish chemist Francis Leslie Scott.