The biological and clinical characteristics of perinatal leukemia differ significantly from those of leukemia in older children, and the prognosis is generally bleak. Once complete remission is achieved, neonates with acute myelocytic leukemia (AML) fare much better than those with acute lymphocytic leukemia (ALL). The results of this study suggest that age, sex, type of leukemia, and cytogenetic findings have a strong influence on outcome. Neonates, particularly females, with pre-B ALL have a much worse prognosis than neonates and older children with this disease. Transient leukemia in the Down syndrome neonate is associated with significant morbidity; close follow-up is recommended for at least the first 3 years of life because of the potential of developing acute leukemia, particularly AMKL (M7). The purpose of this review is to focus on the fetus and neonate in an attempt to determine the various ways leukemia differs clinically and morphologically from the disease occurring in older infants and children and to demonstrate that certain types of leukemia have a poor prognosis compared with those occurring in older children.