RNA interference has become an indispensable research tool to study gene functions in a wide variety of organisms. Because of their high efficacy and specificity, RNA interference-based approaches may also translate into new therapeutic strategies to treat human diseases. In particular, oncogenes such as leukemic fusion proteins, which arise from chromosomal translocations, are promising targets for such gene silencing approaches, because they are exclusively expressed in precancerous and cancerous tissues, and because they are frequently indispensable for maintaining the malignant phenotype. This review summarizes recent developments in targeting leukemia-specific genes and discusses problems and approaches for possible clinical applications.