With the discovery of Philadelphia chromosome, understanding of chronic myeloid leukemia (CML) pathobiology has tremendously increased. Development of tyrosine kinase inhibitors (TKI) targeting the BCR/ABL1 oncoprotein has changed the landscape of the disease. Today, the expected survival of CML patients, if properly managed, is likely to be similar to the general population. Imatinib is the first-approved TKI in CML treatment, and for several years, it was the only option in the frontline setting. Four years ago, second-generation TKIs (nilotinib and dasatinib) were approved as alternative frontline options. Now, clinicians are faced the challenge of making decision for which TKI to chose upfront. Second-generation TKIs have been demonstrated to induce deeper and faster responses compared to imatinib; however, none of three TKIs have been shown to have a clear survival advantage, they all are reasonable options. In contrast, when considering therapy in individual patients, the case may be stronger for a specific TKI. Co-morbidities of the patient and side effect profile of the TKI of interest should be an important consideration in decision making. At present, the cost nilotinib or dasatinib is not remarkably different from imatinib. However, patent for imatinib is expected to expire soon, and it will be available as a generic. Clinicians, then, need to weigh the advantages some patients gain with nilotinib or dasatinib in the frontline setting against the difference in cost. Whatever TKI is chosen as frontline, intolerance, non-compliance, or treatment failure should be recognized early as a prompt intervention increases the chance of achieving best possible response.