Imatinib was developed as the first molecularly targeted therapy to specifically inhibit the BCR-ABL kinase in Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Because of the excellent hematologic and cytogenetic responses, imatinib has moved toward first-line treatment for newly diagnosed CML. However, the emergence of resistance to imatinib remains a major problem in the treatment of Ph-positive leukemia. Several mechanisms of imatinib resistance have been identified, including BCR-ABL gene amplification that leads to overexpression of the BCR-ABL protein, point mutations in the BCR-ABL kinase domain that interfere with imatinib binding, and point mutations outside of the kinase domain that allosterically inhibit imatinib binding to BCR-ABL. The need for alternative or additional treatment for imatinib-resistant BCR-ABL-positive leukemia has guided the way to the design of a second generation of targeted therapies, which has resulted mainly in the development of novel small-molecule inhibitors such as AMN107, dasatinib, NS-187, and ON012380. The major goal of these efforts is to create new compounds that are more potent than imatinib and/or more effective against imatinib-resistant BCR-ABL clones. In this review, we discuss the next generation of BCR-ABL kinase inhibitors for overcoming imatinib resistance.