Events surrounding the development of the ABL kinase inhibitor imatinib (Gleevec) for the treatment of chronic myeloid leukemia (CML) have been extensively chronicled in numerous reviews (1–4). Rather than retell that history here, this chapter reviews recent and emerging issues in the biology and treatment of CML and speculates on future directions. To set the stage, ABL kinase inhibitors have been the mainstay of CML therapy for more than 10 years. This has resulted in a profound shift in the lifespan of CML patients, from a median survival of 5–6 years to an estimated 10–20 years. This success is largely attributable to: (i) a profound reduction in disease burden by 3–4 orders of magnitude with single-agent ABL kinase inhibitor therapy, (ii) durable responses if treatment is initiated early in the course of disease, and (iii) the availability of second-generation ABL inhibitors such as dasatinib, nilotinib, and bosutinib that are effective in many patients who develop resistance to imatinib. While this is an enviable track record of success in cancer, many patients fail to respond optimally or develop multi-drug resistance after sequential treatment with different ABL kinase inhibitors. In addition, this treatment approach commits patients to decades of chronic therapy, with unknown risks of possible late relapse and long-term side effects. An emerging question is whether CML might be cured with the right combination of these or other targeted therapies.