The 60-month update of the Immediate Risk-Stratification Improves Survival (IRIS) study, a trial of standard-dose imatinib in patients with newly diagnosed chronic-phase chronic myelogenous leukemia, showed an 89% projected rate of overall survival. Although this is an enormous improvement over all previously available therapies, approximately 16% of patients experienced failed therapy with imatinib and 7% progressed to accelerated phase or blast crisis. Therefore, resistance continues to be a clinical problem. Exploiting the full potential of imatinib requires close attention to patient response to recognize suboptimal response and treatment failure as early as possible and to make timely adjustments to the therapeutic strategy. This article reviews the definitions and mechanisms of primary and acquired imatinib resistance. Particular emphasis is placed on point mutations in the kinase domain of BCR-ABL as a mechanism of drug resistance, because they highlight important issues related to drug design and the biology of CML. Given the wealth of publications on the subject, including all information was not feasible and choices had to be made.