Recent results of phase II trials which used dasatinib or nilotinib as single agent, or phase III trials comparing second-generation tyrosine kinase inhibitors to imatinib, showed greater potency of these two inhibitors in newly diagnosed chronic myeloid leukemia (CML) patients in chronic phase (CP). In the present review we detail and summarize clinical results of both agents as first-line therapeutic strategy, and also discuss on critical points emerged from the last follow-up of trials comparing new generation tyrosine kinase inhibitors with imatinib. In terms of safety, dasatinib and nilotinib have shown favorable toxicity profile, with peculiar and distinct pattern of adverse events. Based on these results, USA FDA approved both drugs as first-line treatment in newly diagnosed CML: now several therapeutic strategies are available to treat patients at onset of disease. Longer follow-up is however needed to prove the advantages of faster and deeper responses in terms of disease progression compared to imatinib.