The tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of chronic myeloid leukemia (CML). Complete cytogenetic remissions are standard for patients treated in chronic phase; however, treatment outcomes in advanced-phase disease are far less promising. Because hematopoietic cell transplantation is potentially curative in CML and newer TKIs are now available, the use of imatinib necessitates careful monitoring in order to identify cases in which transplantation or alternative TKI therapy might be indicated. Monitoring CML with cytogenetics and molecular methods such as the polymerase chain reaction can define subsets of patients at low or high risk of relapse and progression. In this review, we define the types of tests used to monitor the disease, provide clinically relevant endpoints, and outline guidelines for monitoring patients with CML receiving imatinib therapy.