A subset of patients with chronic myeloid leukemia (CML) who receive imatinib therapy will require alternative therapy at some point owing to safety reasons or lack of efficacy. Achieving an early response with imatinib is protective against treatment failure; second-generation tyrosine kinase inhibitors (TKIs; for example, nilotinib, dasatinib, bosutinib), however, have proven to be efficacious at restoring cytogenetic responses in patients who require subsequent therapy. Response duration, however, is yet to be established and a considerable proportion of patients fail to achieve a clinically meaningful response. A third generation of TKIs is currently undergoing clinical testing for use in patients who fail imatinib and a second-generation TKI. Most of these agents are multikinase inhibitors with activity against a wide variety of BCR-ABL1 mutations, including the highly resistant T315I. The use of second-generation TKIs in the frontline setting seems to provide higher rates of early response compared with imatinib. If these results are confirmed in randomized studies, nilotinib and dasatinib could replace imatinib as standard frontline therapy in CML. Despite the activity of all of the above mentioned agents, curing CML will ultimately depend on the development of agents capable of vanquishing BCR-ABL1-positive CML stem cells. Efforts aimed at achieving this goal are ongoing.