The Abl inhibitor imatinib is a highly effective therapy for patients with chronic myeloid leukemia. Relapses are relatively uncommon in newly diagnosed patients, but are the rule in patients with more advanced disease. Mutations in the BCR-ABL gene are the most common cause of relapse. Working from the imatinib chemical structure, a higher-affinity family member, AMN107, was designed. AMN107 is approximately 20-fold more potent than imatinib, and this translates into improved inhibitory activity against most of the common BCR-ABL mutations. The implications of these results, and the potential role this and other novel ABL inhibitors may have in treating patients with CML, are discussed.