Chronic myeloid leukemia (CML) represents 15% of newly diagnosed leukemia cases. In the United States, about 9000 new CML cases are diagnosed annually . BCR-ABL1-targeted tyrosine kinase inhibitors (TKIs) have vastly changed the treatment and prognosis of CML. Before the introduction of TKIs, allogeneic hematopoietic stem cell transplantation (SCT) was the only known cure for CML. However, due to the advanced age of most patients with CML, this treatment modality was utilized in a small proportion of patients and mortality remained high. The TKIs have transformed CML into a manageable chronic disease state and have decreased the annual mortality to less than 2%. Thus, the prevalence of CML will continue to increase annually until the annual incidence equals the annual mortality, with an estimated potential plateau prevalence of 300,000–500,000 cases in the United States. There are currently five approved TKIs in the United States and in Europe. These include imatinib, dasatinib, nilotinib, bosutinib, and ponatinib. While imatinib changed the landscape of CML treatment drastically, the low rates of molecular response in addition to the high rates of discontinuation due to adverse effects led to the development of second- and third-generation TKIs. These TKIs are more potent than imatinib, have unique adverse effect profiles, and have activity against different molecular mutations, all of which must be considered when choosing a therapeutic agent. This chapter discusses the second- and third-generation TKIs and their role in CML therapy.