The leukemogenic potential of alkylating agents has been known for many years and almost all alkylating agents in clinical use have been shown to increase the risk of leukemia. With these drugs the risk of leukemia appears to increase with increasing patient age, as does the risk of de novo myeloid leukemia in the population. Susceptibility to alkylating agent‐associated leukemia is influenced by the genetic constitution of the patient, and by the nature of the exposure. To illustrate the importance of these factors in etiology of leukemia, this paper discusses the contribution of disorders such as Fanconi anemia and neurofibromatosis to susceptibility to alkylating agent‐associated leukemia. This paper also discusses the contribution of alkylkating agents and other therapeutic exposures in the etiology of leukemias occurring after autologous bone marrow transplant. Med. Pediatr. Oncol. 36:536–540, 2001. © 2001 Wiley‐Liss, Inc.