Acute myeloid leukemia (AML) is a heterogeneous group of diseases typically associated with an aggressive course and generally a poor overall survival (OS). Despite advances in therapy over the past 20 years, long-term survival for patients with AML remains approximately 30% (1). Acute promyelocytic leukemia (APL) represents a distinctive subtype of AML. It accounts for approximately 10% to 15% of all patients with AML and is distinguished from other types by a younger median age (40 vs. 68 years), a unique genetic abnormality, the t(15;17) translocation and the formation of the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) fusion transcript, and most importantly, by the high cure rate achieved with differentiation therapy. Until the late 1980s and early 1990s, APL was considered the most fatal subtype of AML primarily because of a severe coagulopathy often leading to catastrophic hemorrhage early in the natural history of the disease or early in the course of treatment. The discovery that the leukemic promyelocytes from patients with APL were uniquely sensitive to all-trans retinoic acid (ATRA) and that the breakpoint on chromosome 17 that resulted in the development of an abnormal PML-RARα fusion product eventually led to the recognition that disruption of RARα gene product was the major cause of 186maturation arrest in APL (2,3). Currently, APL is associated with several variant chromosomal abnormalities leading to different gene rearrangements. PML-RARα is the product of t(15;17), NPM (nucleophosmin)-RARα is the product of t(5;17)(q35;q21), and is NuMA (nuclear matrix associated)-RARα the product of t(11;17)(q13;q21), all of which lead to a syndrome that is responsive to ATRA. PLZF (promyelocytic leukemia zinc finger)-RARα, the product of t(11;17)(q23; q21), is unresponsive to ATRA. Signal transducer and activator of transcription 5B (STAT5B) is the product of t(17;17)(q11;q21) (4). In addition to cytogenetic variants, molecular variant of the PML-RARα transcript such as bcr1, bcr2, and bcr3 have also been described (5). Advances in the understanding of APL have led to a new strategy in anti-leukemia therapy. Rather than relying on intensive chemotherapy, the treatment of APL focuses now on differentiation therapy to induce remission. Such a strategy results in long-term survival rates of more than 80% (6). This chapter will address the unique biology of APL, the role of ATRA in differentiation therapy and arsenic trioxide (ATO) in inducing apoptosis. Both agents contribute to the remarkable cure rates in APL. In addition, novel strategies such as FLT3 inhibitors, antiangiogenesis agents, monoclonal antibodies, differentiation agents, and histone deacetylase inhibitors will be described.