Arsenic trioxide (As2O3) is an effective therapy for acute promyelocytic leukemia (APL), and there has been promising activity noted in other hematologic and solid tumors. The mechanism of action of As2O3 such as differentiation and apoptosis has prompted study into combination therapy. Furthermore, the connection of the sensitivity of diseases such as APL and multiple myeloma to oxidative damage has allowed the investigation of pharmacologic modulation of the cellular redox state for potentiation of As2O3. Continued study of As2O3 as a single-agent and in combination therapy will allow identification of the safest and most effective treatment regimens for malignant disease.