Multiple myeloma remains an incurable malignancy with a median survival that does not exceed 3 years. At least one third of patients with multiple myeloma fail to respond to induction chemotherapy, and those who initially achieve remission eventually relapse and require additional therapy. Recent reports demonstrating the efficacy of arsenic trioxide in acute promyelocytic leukemia have prompted a revival in the clinical use of this compound. The achievement of clinical responses marked by molecular conversion of the malignant phenotype and remissions in patients who had failed to respond to multiple courses of conventional chemotherapy provided the impetus to explore its use in multiple myeloma. Properties that favor the use of arsenic trioxide are its ability to target selectively malignant cells for apoptosis through enhancementof reactive oxygen species, to induce differentiation, and to inhibit angiogenesis. Multiple events involved in the pathogenesis of multiple myeloma coincide with pathways targeted by arsenic trioxide, and early results have suggested that clinical responses and safety in patients are promising with advanced disease.