Tyrosine kinase inhibitors (TKIs) are now standard up-front therapy for chronic myeloid leukemia (CML). Patients with newly diagnosed chronic-phase CML treated with the TKI imatinib mesylate typically experience a complete cytogenetic remission. Outcomes for patients with advanced-phase disease are distinctly worse. Unfortunately, a small proportion of chronic-phase patients experience relapse during this therapy, and most with advanced-phase disease develop resistance to imatinib mesylate after months of therapy. Hematopoietic cell transplantation remains the only curative approach for CML and can salvage patients with advanced-phase disease. Therefore, physicians must carefully monitor patients with chronic-phase CML treated with TKIs so that they can undergo hematopoietic cell transplant (or treatment with another TKI or experimental therapy) before frank progression occurs. Fortunately, monitoring CML using cytogenetic and molecular methods (i.e., quantitative polymerase chain reaction) effectively defines end points that correlate highly with outcome.