In patients with chronic myeloid leukemia (CML), disease in the initial chronic phase (CP) and subsequent progression are driven by the oncogenic activity of the BCR-ABL fusion kinase. Imatinib, a tyrosine kinase inhibitor of BCR-ABL, has been the mainstay of first-line therapy for CML for 10 years. Although patients with CML-CP respond well to imatinib, those who have delayed reductions in leukemic burden during imatinib therapy, such as not achieving a complete cytogenetic response (CCyR) by 12 months, have an increased risk of disease progression. It has been recognized, with 8 years of observation, that patients who achieve an early major molecular response (MMR) on imatinib have a very low probability of disease progression. Recent randomized phase 3 trials have shown that first-line treatment with dasatinib or nilotinib-more potent BCR-ABL inhibitors-results in significantly higher rates and more rapid achievement of CCyR and MMR in comparison with standard-dose imatinib. These trials suggest that CML treatment can be improved with more potent BCR-ABL inhibition during initial therapy, but further follow-up is needed to confirm that the improved response rates with dasatinib and nilotinib are maintained long term.