Over the past several decades, improvements in chemotherapeutic agents and supportive care have resulted in significant progress in treating patients with acute myeloid leukemia (AML). More recently, advances in understanding the biology of AML have resulted in the identification of new therapeutic targets. The success of all-trans-retinoic acid in acute promyelocytic leukemia and of imatinib mesylate in chronic myeloid leukemia have demonstrated that targeted therapy may be more effective and less toxic when well defined targets are available. At the same time, understanding mechanisms of drug resistance and means to overcome them has led to modification of some of the existing cytotoxic agents. Rational design and conduct of clinical trials is necessary to ensure that the full potential of these new agents is realized. Cancer 2004. © 2003 American Cancer Society.