Acute promyelocytic leukemia (APL) is now the most potentially curable subtype of acute myeloid leukemia in adults because of the introduction of novel approaches in the management of this disease. All-trans-retinoic acid (ATRA)-based therapy is now the first-choice treatment of patients presenting with de novo APL, and clinical studies have shown that nearly all patients who receive ATRA therapy achieve complete remission. However, approximately 20% to 30% of APL patients eventually have relapses with resistance to further ATRA treatment. Arsenic trioxide (As2O3 [ATO]) has been established as highly effective therapy for patients with APL, even for those with disease refractory to ATRA. Furthermore, results of recent studies have suggested a broad therapeutic potential for ATO in the treatment of hematologic malignancies beyond APL. In this review, we discuss the clinical activity and multiple mechanisms of ATO therapy in the management of APL and other hematologic neoplasms.