Kinases have emerged as ubiquitous but highly challenging targets for drug discovery. The human genome has 518 kinases1 and many of these play critical roles in cell growth and apoptosis, making them interesting drug targets for oncology. Kinase targets including epidermal growth factor receptor (EGFRa ), Raf, Src, and breakpoint cluster regionsAbelson's kinase (bcr-Abl) emerged early in the study of oncogenic proteins.2 Despite years of effort involving a compelling breadth of accumulated preclinical design experience (reviewed extensively by Liao and Andrews3,4) and clinical experience (reviewed by LaRusso and Eder 2 ), relatively few kinase inhibitors have been approved (Table 1). As an additional complication, clinical use of these inhibitors has led to the emergence of drug resistant tumors.5-8 In many patients, response to small molecule kinase inhibitors has been followed by tumor resurgence, which rendered these inhibitors less effective than expected. This resistance has been linked to a number of mechanisms that include the amplification of the oncogenic kinase gene9 and alternative signaling pathways or plasticity in signaling.10 However, in many instances, resistance has been traced to individual or groups of mutations in the drug targets that make the tumors unresponsive in the clinic. These mutants alter the binding properties of the drugs as shown by in vitro studies.5 When viewed across multiple cancer targets, the location of these mutations forms a compelling pattern with a number of common mechanisms elucidated with reference to this pattern. Significantly, recent characterization of mutations in the EGFR kinase has included structural and kinetic studies that have challenged assumptions about how individual drug resistance mutants are understood and to what extent mechanisms can be generalized across kinases by homology alone. This review will provide a brief overview of kinase structure and function as it pertains to drug discovery, describe the location and importance of clinical mutations, and review the emerging understanding of their impact based on sequence homology, protein crystal complexes, and biochemical/biophysical information. Underlying this discussion is our appreciation that the current clinical arsenal of small molecule kinase inhibitors only contains the first weapons to be deployed in a long war against drug resistance mutations occurring in multiple kinases that target multiple cancers.