Many members of the protein kinase family have emerged as key targets for pharmacological intervention, most notably in cancer. However, the high sequence and structural homology shared by the more than 500 human protein kinases renders it exceedingly difficult to develop selective inhibitors. Most, if not all, existing inhibitors target multiple protein kinases. Current paradigm suggests that an inhibitor that targets multiple kinases and displays polypharmacology is not only acceptable but also often desirable as a therapeutic agent. However, as we move toward personalized medicine the currently acceptable promiscuity is likely to pose significant hurdles in terms of their therapeutic index, especially for diseases that necessitate long-term drug administration. Moreover, selective inhibitors are the only pharmacologically relevant route toward reagents for the dissection of complex signal transduction pathways. This article provides an overview of recent developments in the design of kinase inhibitors that display increasing selectivity by targeting regions outside the highly conserved ATP-binding pocket. These new approaches may pave the way to potentially new avenues for drug discovery while providing valuable tools for studying signal transduction.