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Alternative approaches for inhibitor development in targeting sites other than the ATP cleft are increasingly being pursued in the search for new therapeutics based on inhibition of protein kinases. While recently approved kinase inhibitor drugs offer benefit in cancer treatment, further advances are required to affect tumor selective cell killing, avoid off-target related toxicities and improve survival rates. Protein-protein interactions involved in kinase regulation and substrate recognition as well as exploiting allosteric pockets, offer the potential for selectivity and avoid decreased efficacy as a result of competition with high intracellular ATP concentrations. We discuss several preliminary examples where regulatory and substrate binding sites present potential druggable interfaces. These include the cell cycle targets which are the cyclin-dependent and polo-like kinases among several others.