BACKGROUND Research into chronic myeloid leukemia (CML) is increasingly focused on the problem of imatinib failure. Dasatinib and nilotinib are both active in chronic- and accelerated-phase CML, including patients with imatinib-resistant or intolerant disease. METHODS This paper reviews advances in tailoring tyrosine kinase inhibition therapy according to patient risk profiles as well as hematologic, cytogenetic, and molecular responses, BCR-ABL mutation status, and emerging predictive factors. RESULTS In addition to identifying specific tyrosine kinase mutations, clinical advances have allowed us to determine patients who are less likely to derive long-term survival benefits from imatinib. CONCLUSIONS Treatment for CML should be individualized and, when resistance to imatinib can be predicted, therapy should be modified so that patients do not progress beyond chronic phase and respond as promptly and deeply as required to maximally reduce risk.