The constitutive activity of the Bcr-Abl tyrosine kinase plays a critical role in the molecular pathogenesis of not only the chronic but also the accelerated and blastic phases of chronic myelogenous leukemia. Therefore, Bcr-Abl tyrosine kinase is a rational therapeutic target in all phases of chronic myelogenous leukemia. Although imatinib mesylate (STI571, Gleevec, Novartis, Basal, Switzerland) produces high rates of complete clinical and cytogenetic responses in the chronic phase, resistance is universal and clinical relapse develops rapidly in the advanced phases of chronic myelogenous leukemia. This resistance has been shown to be caused by specific ATP binding site mutations or amplification of Bcr-Abl gene, resulting in a Bcr-Abl tyrosine kinase that is resistant to further inhibition by imatinib. Alternative (Bcr-Abl-independent) mechanisms driving the growth and survival of the malignant clone may also be responsible for imatinib resistance. Novel tyrosine kinase inhibitors that also target Bcr-Abl tyrosine kinase, or agents that downregulate Bcr-Abl levels regardless of its wild-type or mutant status, may need to be developed clinically for the future therapy of imatinib-resistant chronic myelogenous leukemia.