Chronic myeloid leukemia (CML) is a progressive and often fatal malignancy of the blood. The harbinger of CML is a chromosomal translocation that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase. The advent of imatinib, an inhibitor targeted specifically for BCR-ABL, represented a significant medical advance in CML therapy. However, patients with CML can exhibit varying responses to first-line treatment with imatinib. While most patients respond to treatment, some may experience a loss of response or require treatment discontinuation due to toxicity. Frequent monitoring for resistance or intolerance is a requirement for recognition of suboptimal response. Mutational analysis of the patient's BCR-ABL alleles is also informative and may be predictive of a response to therapy. Published physician guidelines have highlighted these recommendations, but it is not clear if these guidelines are universally followed. One option in patients showing poor response to standard-dose imatinib of 400 mg is to escalate the dose. However, this option should be reserved for patients with minimal disease burden. Clinically available options mainly include second-generation tyrosine kinase inhibitors, such as dasatinib and nilotinib. Allogenic stem cell transplantations (for eligible patients) also should be considered. The disease and patient characteristics at the time of imatinib failure should be evaluated before choosing second-line therapy to optimize the therapeutic benefit without unnecessary delay.