Imatinib is the cornerstone of therapy in chronic myelogenous leukemia (CML) and a model for the development of novel agents directed at specific targets. The results of imatinib therapy continue to improve with approaches such as higher doses of imatinib and, possibly, with combinations of imatinib and interferon-alpha with or without cytarabine. There are multiple targets with agents directed to them that may prove to be synergistic with imatinib. These approaches are attractive, particularly when dealing with imatinib resistant CML, to prevent resistance and improve the probability of cure. The continued understanding of the biology of CML and mechanisms of resistance to imatinib and the ability to develop target-specific therapies should lead to the increased probability of cure for most patients who have CML.