Kinase inhibitors are plagued by a lack of specificity. Now in the 21 September Nature Bishop et al. tackle the problem by building on their earlier work, in which they modified the ATP-binding sites of Src-family tyrosine kinases to accept either nucleotide analogs or modified kinase inhibitors. In the new work the researchers mutate kinases from four distinct kinase families by replacing a bulky residue with a small residue. This change provides enough room for the binding of inhibitor analogs, which are larger than their parent inhibitors and thus do not inhibit wild-type kinases (Nature 2000, 407:395-401). The in vivo specificity is demonstrated using expression arrays. Most kinases contain a bulky residue analogous to the one mutated in this study, and thus should be amenable to the kinase-sensitization strategy.