The leukemias are complex diseases with a wide range of clinical, morphologic, biologic, molecular, and clinical features and a consequent array of possible responses to any given intervention. Although progress has been made in the management of the leukemias, most patients who fail to respond to front-line therapies or who relapse after an initial response die from progressive disease. The balance between efficacy and toxicity of traditional cytotoxic therapies is increasingly unacceptable. As a consequence, the search for therapeutic advances is more focused on affecting the critical steps involved in the development, propagation, and mutation of malignant clones. This article briefly reviews current data on some agents being developed for the treatment of patients with leukemia, with an emphasis on modulators of angiogenesis, inhibitors of the ubiquitin-proteasome pathway, novel nucleoside analogues, and gene hypomethylation agents.