Myelodysplastic syndrome (MDS) is a heterogeneous bone marrow disorder primarily affecting older adults, for whom the only curative therapy, bone marrow transplantation, is rarely an option. New therapies, or novel applications of historical therapies, are desperately needed. Arsenic trioxide (ATO), which acts through pro-apoptotic, antiproliferative, and anti-angiogenesis mechanisms, has been used successfully to treat a variety of hematologic malignancies, including MDS. As monotherapy or in combination with other agents, it can effect hematologic improvement in 22% to 26% of patients, with tolerable side effects. MDS patients whose cells express the EVI1 mutation in particular may derive benefit from this therapy.