Imatinib is a molecularly targeted therapy that inhibits the oncogenic fusion protein BCR-ABL, the tyrosine kinase involved in the pathogenesis of chronic myelogenous leukemia (CML). Selective inhibition of BCR-ABL activity by imatinib has demonstrated efficacy in the treatment of CML, particularly in chronic phase. Some patients, however, primarily those with advanced disease, are either refractory to imatinib or eventually relapse. Relapse with imatinib frequently depends not only on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL-independent disease progression not amenable to imatinib inhibition. Results from phase 2/3 trials suggest that rates of resistance and relapse correlate with the stage of disease and with the monitoring parameters--hematologic, cytogenetic and molecular response. These observations and more recent trials with imatinib, combined with insights provided by an increased understanding of the molecular mechanisms of resistance, have established the rationale for strategies to avoid and overcome imatinib resistance in the management of CML patients. To prevent resistance, early diagnosis and prompt treatment with appropriate initial dosing is essential. Management of resistance may include therapeutic strategies such as dose escalation to achieve individual optimal levels, combination therapy, as well as treatment interruption.