Protein kinases have emerged as one of the most frequently targeted families of proteins in drug discovery. While the development of small-molecule inhibitors that have the potency and selectivity necessary to be effective cancer drugs is still a formidable challenge, there have been several notable successes in this area over the past decade. However, in the course of the clinical use of these inhibitors, it has become apparent that drug resistance is a recurring problem. Because kinase inhibitors act by targeting a specific kinase or set of kinases, there is a strong selective pressure for the development of mutations that hinder drug binding but preserve the catalytic activity of these enzymes. To date, resistance mutations to clinically approved kinase inhibitors have been identified in a number of kinases. This review will highlight recent work that has been performed to understand how mutations in the kinase catalytic domain confer drug resistance. In addition, recent experimental efforts to predict potential sites of clinical drug resistance will be discussed.