Therapy with imatinib mesylate is a standard of care for most patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML). However, resistance or intolerance to imatinib develops in a considerable number of patients leading to relapse or discontinuation of treatment. Nilotinib is a rationally designed second-generation tyrosine kinase inhibitor (TKI) with improved affinity and specificity against the BCR-ABL kinase, when compared with imatinib. Considerable efficacy after imatinib failure has been demonstrated in clinical trials leading to nilotinib's current approval as second-line therapy for CML in chronic and accelerated phase (AP). The role of nilotinib as first-line treatment for CML, in combinatorial strategies and in the context of specific BCR-ABL mutations, requires future studies.