Arsenic is a natural substance that has been used medicinally for over 2,400 years. In the 19th century, it was the mainstay of the materia medica. A solution of potassium arsenite (Fowler's solution) was used for a variety of systemic illnesses from the 18th until the 20th century. This multipurpose solution was also primary therapy for the treatment of chronic myelogenous leukemia until replaced by radiation and cytotoxic chemotherapy. The past 100 years have seen a precipitous decline in arsenic use and, by the mid-1990s, the only recognized indication was the treatment of trypanosomiasis. Much of this decline was due to concerns about the toxicity and potential carcinogenicity of chronic arsenic administration. The rebirth of arsenic therapy occurred in the 1970s when physicians in China began using arsenic trioxide as part of a treatment for acute promyelocytic leukemia (APL). Their accumulated experience showed that a stable solution of arsenic trioxide given by intravenous infusion was remarkably safe and effective both in patients with newly diagnosed APL leukemia and in those with refractory and relapsed APL. The mechanisms of action of arsenic derivatives in this disease and other malignancies are many and include induction of apoptosis, partial cytodifferentiation, inhibition of proliferation, and inhibition of angiogenesis. Molecular studies and ongoing clinical trials suggest that, as a chemotherapeutic agent, arsenic trioxide shows great promise in the treatment of malignant disease.