The coincidence of trisomy 21 and leukemia has interested clinicians since it was first reported by Brewster and Cannon (Brewster & Cannon, 1930). Although the understanding of both of these disorders has broadened since the first report of their association, new techniques in molecular biology and molecular genetics enhance the likelihood that the details of this relationship may soon be better understood. In this review, consideration will be given to the occurrence in Down syndrome of congenital leukemia, neonatal transient leukemoid reaction (alternative terms include neonatal myeloproliferative disorder, transient leukemia, pseudoleukemia), and acute leukemia. The epidemiology of leukemia in association with Down syndrome and the significance of this association to more general concerns in both Down syndrome and leukemia will be discussed. Finally, some areas for future research will be suggested.