Molecular discoveries and clinical advances over the past few decades have made the treatment of chronic myeloid leukemia (CML) one of the great success stories of modern medicine. Before the 1980s, the focus was on maintaining normal white blood cell counts with agents such as hydroxyurea and busulfan. With the use of interferon, treatment strategies turned more toward cytogenetic remission. In 1998, targeted therapy was introduced to this setting with the first studies of imatinib mesylate. Since then, treatment objectives have shifted toward the attainment of molecular remission. In this review, we consider the variety of approaches to treating CML, efforts to minimize treatment failures, and possible future directions in therapy.