Patients with Down syndrome (DS) display a unique spectrum of malignancies, with a 10- to 20-fold higher risk of acute leukemias, and a markedly lower incidence of solid tumors. This review discusses the current understanding of the basis for this distinctive pattern of cancer incidence and the clinical and biologic features of the malignant disorders most frequent in DS individuals: transient myeloproliferative disease, acute megakaryoblastic leukemia, and acute lymphoblastic leukemia. We also review distinctive pharmacogenetic issues, highlighting the differential chemosensitivity and toxicity profiles of DS patients compared with the general population, and epidemiologic studies of protective and adverse environmental risk factors for the development of leukemia.