Research conducted over the last two decades has yielded a detailed understanding of the molecular lesions that contribute to the malignant transformation of hematopoietic stem cells and committed progenitors into the various forms of acute and chronic leukemia. Although our understanding of the molecular pathology of leukemia remains incomplete, the information gained to date has had a profound impact on the way these malignancies are both diagnosed and monitored during therapy. More recently, targeted therapies have been developed against some of the identified genetic lesions. These therapies have led to significant improvements in patient outcomes while simultaneously decreasing therapy-related toxicity. With the advent of genome-wide methods to define the total complement of genetic and epigenetic lesions involved in leukemogenesis, new targeted therapies can be anticipated. This review highlights some of the targeted therapies that are presently being used to treat hematopoietic malignancies and describes some of the recent advances that should have a significant impact on the development of future target therapies.