The outlook for newly diagnosed patients with chronic myeloid leukemia (CML) in the imatinib era is excellent for most patients. However, imatinib failure is observed in around 25%-30% of patients. With the availability of second-line tyrosine kinase inhibitor therapy and/or allogeneic transplantation, many of these patients with imatinib failure can still achieve durable cytogenetic and molecular responses. Early evidence of imatinib resistance, when the biology of the emerging leukemia might still be relatively favorable, is the best time to switch to second-line therapy. Close cytogenetic and molecular monitoring will facilitate early intervention in appropriate cases. However, caution should be used when interpreting minimal residual disease data, and the danger of inappropriate changes in therapy based on assay fluctuations should be recognized. A significant increase in the level of BCR-ABL to a level > 0.1% on the international scale (major molecular response) should prompt a repeat BCR-ABL assay, a mutation screen, and possibly marrow cytogenetics. What constitutes a significant increase depends on the laboratory-specific measurement reliability. The possibilities of poor compliance or drug interactions should be considered. If the repeat BCR-ABL assay, fluorescence in situ hybridization assay, or cytogenetics confirms loss of complete cytogenetic response or if a mutation is identified, a dose increase or a switch in therapy to a second-line kinase inhibitor might be indicated. At least until complete molecular response is achieved, regular real-time polymerase chain reaction monitoring reinforces the fact that leukemia is still present and that compliance is a challenge that requires ongoing vigilance from the patient and the clinician.