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Aside from bone marrow transplantation, a definitive cure for Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) has yet to be developed. Although Imatinib, the first molecularly targeted drug developed for CML has achieved a remarkable success, the emergence of resistance to this agent mitigates the prospect of a cure for this leukemia. Though a variety of resistance mechanisms can arise, in the majority of patients resistance coincides with reactivation of the tyrosine kinase activity of the BCR-ABL fusion oncoprotein. This can result from gene amplification and, more importantly, point mutations that disrupt the bind of imatinib to BCR-ABL itself. In this review, we aim to define and illuminate mechanisms of resistance and describe how drug resistance is shedding new light on kinase domain regulation.In light of recent studies and publications, it is now clear that Imatinib exerts its inhibitory action by stabilizing the inactive non ATP-binding conformation of BCR-ABL and that mutations even outside the kinase domain can lead to enhanced autophosphorylation of the kinase, thereby stabilizing the active conformation that resists imatinib binding. So far, 25 different substitutions of 21 amino acid residues of BCR-ABL have been detected in CML patients. In addition, it has been recently illustrated that mutations preexist the onset of treatment and that some confer a more aggressive disease phenotype. Finally it has been shown that molecular remission is almost never reached through Imatinib therapy.The most common mechanism of relapse for CML patients treated with Imatinib is the appearance of point mutations in the BCR-ABL oncogene that confer resistance to this drug. Insights into the emerging problem of resistance should promote the rational development of alternative, synergistic, and potentially curative treatment strategies.