Children with Down syndrome (DS) present unique challenges to the pediatric hematologist-oncologist. They have a 10-20 fold increased risk of leukemia, and exhibit a unique spectrum of diseases and treatment-related toxicities associated with their somatic genetic abnormality. This symposium will review current clinical approaches and recent insights into the biology of acute myeloid leukemia (AML), transient myeloproliferative disorder (TMD), and acute lymphoblastic leukemia (ALL) in patients with DS. Unique pharmacologic issues arising in the chemotherapeutic treatment of leukemias in DS patients will also be discussed, including distinctive toxicities.