The clinical success of the kinase inhibitor imatinib for the treatment of chronic myeloid leukemia (CML) is partially due to the high degree of selectivity it shows for the tyrosine kinases BCR-ABL, Abl, c-Kit, and PDGFR. However, how imatinib is able to discriminate between closely related kinases is not fully understood. Seeliger and colleagues present a series of inhibitors (DSA compounds) that equipotently inhibit the tyrosine kinases Abl and c-Src and are designed to have the same binding mode as imatinib. The cover image shows the crystal structure of Src Thr338Ile in complex with one of these inhibitors, DSA1. This study points to the mechanism underlying imatinib selectivity, the effects of resistance mutations, and provides a new series of inhibitors that are able to block the activity of many of the most clinically relevant BCR-ABL mutants. These compounds may prove to be valuable leads for the development of new therapeutics for the treatment of drug-resistant CML. For details, see the article by Seeliger and colleagues on page 2384 of this issue.