Because of their outstanding efficacy and low toxicity, tyrosine kinase inhibitors (TKIs) have replaced allogeneic hematopoietic cell transplant (HCT) as the standard frontline therapy for patients with newly diagnosed chronic myeloid leukemia (CML). Until a decade ago, HCT was the preferred treatment for CML, with 5-year overall survival rates of approximately 80%, 40%, and 20% for patients in chronic, accelerated, and blast crisis phases, respectively. Relapse after transplant is a problem for patients who undergo transplant in advanced phase disease and those undergoing a T-depleted transplant. Until the introduction of TKIs, therapy for relapsed CML after transplant relied on interferon and/or donor leukocyte infusion (DLI). Although effective in inducing remission, DLI is associated with clinically significant graft-versus-host disease or myelosuppression, with an accompanying treatment-related mortality of 5% to 20%. TKIs have emerged as an attractive alternative therapy for persistent or relapsing CML after HCT. Similar to DLI, the effectiveness of TKI posttransplant is largely determined by the phase of disease at relapse, showing very good response in patients experiencing relapse in the chronic phase, with high rates (>60%) of hematologic and cytogenetic remissions, but less favorable outcomes in patients with advanced disease, with only a minority experiencing durable cytogenetic or molecular remissions. Molecular monitoring of the BCR-ABL chimeric mRNA posttransplant is important for early detection of patients at high risk of relapse.