The introduction of all-trans retinoic acid in 1985 combined with anthracycline-based chemotherapy has revolutionized the prognosis of acute promyelocytic leukemia (APL) with current complete response rates of more than 90% and cure rates of approximately 80%. The subsequent advent of arsenic trioxide in 1994 marked an additional milestone in APL treatment and has inspired the design of rationally targeted, chemotherapy-free front-line treatment regimens without compromising the excellent outcome achieved by anthracycline-containing protocols. APL is, therefore, a unique subtype of acute myeloid leukemia potentially curable with targeted therapies without any exposure to conventional DNA-damaging chemotherapy. Cure rates of APL can be further increased by implementing management strategies to reduce early hemorrhagic deaths, which remain the major cause of treatment failure with the current therapy.