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Although imatinib has been used as frontline therapy for chronic myeloid leukemia (CML) for nearly a decade, current debate is focused on the incorporation of newer tyrosine kinase inhibitors (TKIs) at diagnosis in light of recent US Food and Drug Administration approval of nilotinib and dasatinib for initial therapy in chronic-phase CML. Articles were identified through a PubMed search and a review of abstracts from relevant hematology congresses. Additional information was provided from the authors' libraries and expertise. With several therapies now available, it is crucial to carefully define and monitor response in patients with CML to determine whether their treatment is appropriate and is providing an optimal outcome. Different patterns of response to TKI treatment have been recognized, ranging from best-case scenarios of rapid and unwavering response to difficult situations of intolerance and resistance, either primary or secondary. Patients who develop resistance to imatinib are advised to switch to second-generation TKIs. Although specific mutations in the breakpoint cluster region–v-abl Abelson murine leukemia viral oncogene (BCR-ABL) kinase domain may guide treatment selection in such scenarios, the choice is driven by other factors in the majority of patients, including the toxicity profiles of the newer TKIs as well as a patient's comorbidities. Cancer 2011;. © 2011 American Cancer Society.The treatment paradigm for patients with chromic myeloid leukemia is changing rapidly with the availability of newer tyrosine kinase inhibitors (TKIs). The results of this review indicated that the second-generation TKIs nilotinib and dasatinib are recommended for patients with resistance to imatinib and are being used increasingly to treat patients who experience persistent, moderate toxicity with imatinib.