The BCR-ABL inhibitor imatinib revolutionized the treatment of chronic myeloid leukemia (CML). However, resistance and intolerance to imatinib have emerged as substantial clinical issues. The mechanisms underlying resistance are multifactorial and may include mutations in the kinase domain of BCR-ABL, increased production of BCR-ABL, or activation of BCR-ABL-independent pathways. Two second-line BCR-ABL inhibitors are now approved for treatment of patients with resistance or intolerance to imatinib. Dasatinib is a dual BCR-ABL/Src-family kinase (SFK) inhibitor approved for patients with imatinib-resistant and -intolerant CML in any phase and Ph+ ALL. Nilotinib, an analogue of imatinib, is approved for the treatment of imatinib-resistant or -intolerant patients with chronic or accelerated phase CML. Both agents have shown significant clinical activity in patients with imatinib-resistant or -intolerant CML, and their approval represents a major advancement in the treatment options available. Choosing the most appropriate treatment after imatinib failure may be critical in attaining the best possible long-term prognosis. The presence of certain disease characteristics (e.g. specific BCR-ABL mutations) or patient comorbidities may facilitate more effective treatment. In this review, we discuss mechanisms of imatinib resistance and preclinical and clinical data with dasatinib and nilotinib which may have potential use for guiding second-line treatment decisions.