Arsenic trioxide (ATO) has a long history of efficacy as an antileukemic agent. However, with the advent of modern therapy, it had been relegated to a historical footnote. In the 1990s, investigators in China reported that ATO was safe and had dramatic efficacy in patients with acute promyelocytic leukemia (APL). Preclinical investigations indicate that the biological targets of this novel drug extend to a variety of malignancies other than APL and include induction of apoptosis, nonterminal differentiation, and suppression of proliferation and angiogenesis. The myelodysplastic syndromes (MDSs) present a particular therapeutic challenge. Ineffective hematopoiesis predominates in patients with low-grade prognostic scores. The survival of those patients with high-grade disease is compromised by a high risk of leukemia transformation. Although a number of therapeutic options have been investigated, none has emerged as being broadly efficacious and having an acceptable toxicity profile. No drug has yet received approval by the Food and Drug Administration for this indication. Biologic features of MDS, which include accelerated apoptotic potential, limited maturation capacity, and medullary neovascularity, create a strong scientific rationale for the investigation of ATO in MDS. This report describes the history and scientific basis for ATO treatment of hematologic malignancies, enumerates the potential benefits of ATO in MDS, and discusses the direction of ongoing trials of this novel antineoplastic agent.