Fanconi anemia (FA) is an autosomal recessive disorder characterized clinically by a progressive pancytopenia, diverse congenital abnormalities, and increased predisposition to malignancy. Although a variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, the unique sensitivity of FA cells to the clastogenic effect of DNA cross-linking agents such as diepoxybutane (DEB) can be used to facilitate the diagnosis. We review all cases of FA reported to have leukemia, preleukemia, or a bone marrow (BM) clonal chromosomal abnormality and include for the first time an analysis of these conditions observed in patients in the International Fanconi Anemia Registry (IFAR). The incidence of acute myelogenous leukemia (AML) in FA patients is more than 15,000 times that observed in children in the general population. Cytogenetic studies of FA-associated leukemias disclose a high frequency of monosomy 7 and duplications involving 1q. There were no occurrences of t(8;21), t(15;17), or abnormalities of 11q, which are associated with M2, M3, and M5 leukemias, respectively, but not with preleukemia. Development of leukemia in FA patients was associated with an exceedingly poor prognosis, with a mean age of death of 15 years. We suggest that all FA patients may be considered preleukemic and that this disorder presents a model for study of the etiology of AML.