Most patients with chronic myeloid leukemia (CML) receiving treatment with BCR-ABL1 tyrosine kinase inhibitors (TKIs) will achieve favorable responses. Moreover, TKI therapy enables patients to experience long-term survival, with survival rates similar to those of individuals without CML. This enhanced survival has resulted from the availability of multiple BCR-ABL1 TKIs with efficacy, not only in frontline treatment, but, importantly, also in second- and third-line treatment. We have reviewed the changes in long-term outcomes in the era of TKI therapy and how these changes have affected treatment practices. We discuss the development of imatinib, the first BCR-ABL1 TKI, followed by newer TKIs, including nilotinib, dasatinib, bosutinib, and ponatinib. We consider the key studies that led to their development as frontline or later-line therapies, their safety profiles, and their effect on improving patient outcomes. With these improved outcomes, the definition of an optimal response has become more stringent, and treatment monitoring strategies have changed. Second-line patient populations have evolved from those with resistance to, or intolerance of, imatinib to those with moderate responses to, or low-grade adverse events with, imatinib. Although all TKIs are associated with high survival rates, newer TKIs have been associated with lower disease progression rates and, importantly, deeper treatment responses and, potentially, a greater chance of future treatment-free remission. Finally, we consider the unmet needs of patients with CML, including the challenges remaining for those without optimal responses during TKI therapy and new therapies and strategies to identify such patients at diagnosis.