In 2006, most newly diagnosed patients with chronic myeloid leukemia (CML) underwent first-line, molecular-targeted therapy with the Bcr-Abl tyrosine kinase inhibitor, imatinib. The expectation was that the vast majority of these patients would exhibit a complete cytogenetic response on imatinib alone. Studies of patients with acquired imatinib resistance revealed that Bcr-Abl signaling is reactivated at the time of resistance, predominantly because of mutations that interfere with drug binding in the kinase domain of Bcr-Abl. The knowledge that Bcr-Abl remains the optimal target for treating imatinib-refractory CML has driven an already highly successful search for alternative approaches to restore target inhibition. Here, we review the current state of affairs in the realm of controlling drug resistance in CML, including cutting-edge strategies to reign in Bcr-AblT315I, which is cross resistant to imatinib, as well as the "next generation" Bcr-Abl inhibitors, nilotinib and dasatinib. We also critically assess the role of combined Abl kinase inhibitor therapy in overcoming resistance and provide recommendations for monitoring patients for kinase domain mutations.