In patients with chronic myelogenous leukemia (CML) mutations of the BCR-ABL kinase domain (KD) have been identified as the leading cause of acquired resistance to imatinib, while the mechanisms underlying the persistence of minimal residual disease (MRD) are unknown. In this issue of Blood, Chu and colleagues report several patients with KD mutations at the time of complete cytogenetic response (CCR), implicating mutations as a cause of disease persistence.