With the use of tyrosine kinase inhibitors (TKIs), chronic myelogenous leukemia in chronic phase (CML-CP) has been transformed into a non-fatal chronic disease. Hence, "treatment-free remission (TFR)" has become a possible treatment goal of patients with CML-CP. Currently, four types of TKIs (imatinib, nilotinib, dasatinib, and bosutinib) are used as the first-line treatment for newly diagnosed CML-CP. However, the second-generation TKI (2GTKI), the treatment response of which is faster and deeper than that of imatinib, is not always recommended as the first-line treatment for CML-CP. Factors involved in TKI selection in the first-line treatment of CML-CP include not only patients’ medical background, but also patients’ choice regarding the desired treatment goal (survival or TFR?). Therefore, it is important that clinicians select an appropriate TKI to successfully achieve the desired treatment goal for each patient, while minimizing the development of adverse events. This review compares the pros and cons of using imatinib and 2GTKI for TKI selection as the first-line treatment for CML-CP, mainly considering treatment outcomes, medical history (i.e., desire for pregnancy, aging factor, and comorbidity), and cost. The optimal use of 2GTKIs is also discussed.