After World War II, he began working together with Jerome Karle, a physical chemist, at the Naval Research Laboratory in Washington, D.C.. He also enrolled in the Ph.D. program at the University of Maryland, College Park. They used their mathematics and physical chemistry skills to solve the phase problem of X-ray crystallography. By 1955, he had received his Ph.D. in mathematics, and they had worked out the direct methods in X-ray crystallography. Their 1953 article, "Solution of the Phase Problem I. The Centrosymmetric Crystal", contained the main ideas, the most important of which was the introduction of probabilistic methods.
In 1970 he joined the Medical Foundation of Buffalo, becoming its Research Director in 1972. At this time he developed the neighborhood principle and extension concept. These theories were further developed during the following years.