Acute promyelocytic leukemia (APL) has become the most curable subtype of acute myeloid leukemia in adults. It represents the only established example of successful differentiation therapy. With current therapy which includes all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy for induction, anthracycline-based consolidation and maintenance with ATRA and/or low-dose chemotherapy, approximately 75-85% of patients with acute promyelocytic leukemia (APL) remain alive and disease-free at 5 years, and most patients are likely to be cured, an unprecedented achievement in the field of hematologic malignancies. However, several causes for failure to be cured need to be addressed. The first is early death which occurs in approximately 10% and is frequently attributable to hemorrhage due to the characteristic coagulopathy. The second is relapse, particularly in intermediate- and high-risk patients. Analyses of new prognostic factors may permit refinement of current risk classification and identify patients warranting alternative therapy. Finally, long-term consequences of current treatment will be important to recognize, including delayed cardiomyopathy, extramedullary relapse related to sanctuary sites, and the potential for second malignancies. For patients who do relapse, arsenic trioxide appears to be the treatment of choice since the majority of patients achieve a second complete morphologic, cytogenetic, and even molecular remission. While some patients achieving a second complete remission have prolonged disease-free survival with consolidation and maintenance arsenic, high-dose chemotherapy with autologous hematopoietic stem cell transplantation appears to offer the highest likelihood of cure. Such a strategy or anti-CD33 antibodies, recently shown to be active in APL, might be considered for high-risk patients in first remission.