Imatinib has shown considerable success in treating Philadelphia Chromosome positive chronic myelogenous leukemia patients. Continuing treatment has resulted in the emergence of a collection of single amino acid substitutions mapped to the Abl kinase domain of BCR-Abl that render patients insensitive to imatinib therapy. This figure presents a high resolution crystal structure of the catalytic domain of BCR-Abl containing a single point mutation (His396Pro) that makes BCR-Abl resistant to inhibition by imatinib. The protein is bound to the small molecule inhibitor VX-680. Despite the lack of phosphorylation, the mutant enzyme is in a catalytically active conformation. The location of the mutation at a distance from the drug binding site illustrates how resistance can arise as a consequence of destabilization of the inactive conformation of Abl that is selectively targeted by imatinib. VX-680 is also active against the Thr315Ile mutation in the ion of the enzyme. This mutation is a very commonly occurring one, and the avoidance of the recognition of the active conformation by VX-680 explains the effectiveness of this compound against mutant forms of BCR-Abl that are insensitive to imatinib and other inhibitors. For details, see the article by Young et al. on page 1007 of this issue.