The introduction of imatinib mesylate (Gleevec) has dramatically changed the management and prognostic outlook of patients with chronic myeloid leukemia (CML). Despite the outstanding results achieved with imatinib, approximately 20% to 30% of patients may either not respond to therapy or eventually develop resistance or intolerance to the drug. Resistance to imatinib is mediated to a great extent by the emergence of mutations within the tyrosine kinase domain of the BCR-ABL oncogene. A growing number of tyrosine kinase inhibitors (TKIs) with different pharmacokinetic and pharmacodynamic profiles are currently being investigated in clinical trials to determine their efficacy against CML resistant to imatinib therapy. The leading examples of this group of second-generation TKIs are nilotinib (Tasigna) and dasatinib (Sprycel). This review addresses the causes and consequences of imatinib resistance and current management of refractory CML with the second-generation TKIs.