Platelet function is tightly regulated by a series of surface-expressed G protein-coupled receptors (GPCRs). The pharmacological targeting of these receptors has been proven to be an effective strategy for treating and preventing arterial thrombosis associated with coronary atherosclerosis. There is still, however, high interpatient variability in therapeutic response and adverse bleeding side effects to antithrombotic drug therapy. A more detailed understanding of the molecular mechanisms regulating GPCR and therefore platelet function can only further optimize the use of existing antiplatelet drugs and help in the development of new therapies. The identification and characterization of rare, function-disrupting mutations within key platelet proteins in patients with bleeding disorders has proved a useful strategy in furthering our understanding of these key clinical targets. In this chapter, the use of integrated functional genomics strategies that have contributed important structure-function information about platelet GPCRs is discussed. There is specific emphasis placed upon purinergic and thromboxane A2 receptors, through which the potential implications for pharmacotherapy and for understanding the molecular basis of mild bleeding disorders are discussed.