Born in Chester, Vermont, Cram was educated at the University of Nebraska and at Harvard, where he completed his PhD in 1947. He moved immediately to the University of California, Los Angeles, where he served as professor of chemistry from 1956 until 1995.

In 1963 Charles Pedersen announced his discovery of the first of the crown ethers. Cram, it was reported, spent the next 48 hours in his laboratory fiddling with model kits and making a variety of new structures. He soon came to see that crown ethers could be modified in such a way as to distinguish between different forms of chiral molecules, i.e. molecules and their mirror images. By 1973 he had succeeded in devising crown ethers that could identify optically active amino acids. Cram introduced the name ‘host–guest’ chemistry to describe such reactions.

For his work in this new field Cram shared the 1987 Nobel Prize for chemistry with Pedersen and J-M. Lehn.