Long-term follow-up of clinical studies has demonstrated the efficacy of imatinib therapy in newly diagnosed chronic phase-chronic myeloid leukemia patients (CML). However, recent updates of two separate randomized Phase III studies demonstrated higher complete cytogenetic and major molecular response rates with dasatinib and nilotinib compared with imatinib 400 mg/day. Hence, for newly diagnosed chronic phase-CML patients there are multiple treatment options, including standard-dose imatinib, high-dose imatinib, and combination therapy of imatinib and interferon, dasatinib and nilotinib. This article critically analyzes the current literature and provides guidelines for the management of newly diagnosed CML. Disease and therapy-related prognostic factors, which may aid in the selection of therapeutic strategies to enable optimal treatment outcomes, are discussed. In addition, we provide commentary on the therapeutic options for patients who fail imatinib therapy.