Imatinib has revolutionized the treatment of chronic myelogenous leukemia (CML). Given the high rates of complete cytogenetic remission achieved with imatinib therapy, molecular monitoring of BCR-ABL transcript levels by real-time quantitative polymerase chain reaction has become the method of choice to assess the amount of residual disease below the cytogenetic threshold. BCR-ABL transcript levels measured at specific times during therapy may predict durable cytogenetic remission and prolonged progression-free survival or, on the contrary, failure and suboptimal response, thus directing clinical decisions. Recently, recommendations have been established for harmonizing the methodologies used to measure BCR-ABL transcripts in patients with CML, allowing results to be expressed on a standardized comparable international scale. Rising levels of BCR-ABL transcripts indicate the need for an analysis of kinase mutations, the major mechanism of imatinib resistance. The early detection and the characterization of these mutations may allow timely and appropriate treatment to overcome resistance.