The biology of chronic myeloid leukemia (CML) has enabled pioneering studies with targeted therapies. BCR-ABL inhibition with imatinib results in high levels of efficacy in patients with newly diagnosed CML in chronic phase (CP), but an estimated 35% of patients could benefit from more effective treatment. Several novel treatment strategies are being investigated in newly diagnosed CML-CP. These strategies include upfront treatment with next-generation tyrosine kinase inhibitors, such as dasatinib, nilotinib, or bosutinib, which also target BCR-ABL but with increased in vitro potency compared with imatinib, and possibly a reduced potential for resistance. Recent in vitro studies have shown that short-term exposure to dasatinib or continuous exposure to imatinib result in equivalent levels of apoptosis, indicating that potent intermittent inhibition is a successful strategy for improving dasatinib tolerability. Modified imatinib regimens are also being investigated in newly diagnosed CML-CP, including higher doses and combination with alternative classes of agents, such as interferon. Existing data suggest that both newer agents and combination approaches can improve treatment responses compared with standard imatinib treatment, although further data are needed, particularly from ongoing phase 3 trials, before the standard of care is revised.