The N-nitrosoureas are the most active of a variety of N-nitroso compounds tested against L1210 leukemia in mice. Structure-activity studies show that the N-(2-chloro(or fluoro)ethyl)-N-nitrosoureido grouping is necessary for high-level activity in this test system, but a variety of carrier groups can be attached to the N'-nitrogen of the urea. For high-level activity against solid tumors in rodents, eg, the Lewis lung adenocarcinoma, the N'-substituent must be a cyclohexane ring, and the most active of these compounds are substituted at position 4 of the ring. The chemistry involved in the synthesis and reactions of the nitrosoureas is described. The possible relationship of the chemically reactive species generated by the decomposition of the nitrosoureas under in vivo conditions to biologic activity is discussed.