The role of molecular monitoring for patients with chronic myeloid leukemia (CML) is multifaceted. Milestone measurements up to 18 months of first-line imatinib therapy are prognostic and provide warning signals of suboptimal response. Serial measurements for patients with a complete cytogenetic response determine ongoing treatment efficacy or signal pending relapse. The pattern of molecular and cytogenetic response is generally comparable, but only cytogenetic analysis can monitor for the acquisition of clonal abnormalities and has an important role in case of loss of molecular response. For patients treated with imatinib, a rising level of BCR-ABL is a trigger for kinase domain mutation analysis. The characterization of BCR-ABL inhibitor-resistant mutations is important to direct therapeutic intervention because it is now apparent that each resistant mutation functions as a distinct protein with unique biological properties that may confer a gain or loss of function. The benefit to patients of regular molecular analysis is a reassurance of ongoing response using the most sensitive of techniques or a potential improvement in outcome for those where relapse is indicated early. However, despite the obvious benefits of molecular analysis, the measurement techniques may not be quite ready for acceptance into the routine clinical monitoring practices of all clinicians. The challenge now is to standardize and simplify the method so that it can be readily and reliably incorporated into routine laboratory testing procedures.