Platelets are the primary cell mediator of thrombosis. A deficiency of platelets can result in severe bleeding defects. “Overactive” platelets contribute to life-threatening outcomes in diseases such as heart attack, stroke, and cancer. The use of platelet inhibitors for thrombosis prevention must therefore seek a delicate balance between inhibiting platelet activation and an associated increased bleeding risk. There are currently few platelet inhibitors clinically available, making the search for novel anti-platelet drug targets a major research priority. Several newly identified pathways of platelet activation may hold hope in this area. In addition, important roles for platelets beyond hemostasis have been discovered. Platelets have recently been described as mediators of diverse inflammatory diseases such as arthritis, hepatitis, malaria, and atherosclerosis. This has heightened the need to broaden our understanding of platelet functions and platelet-derived inflammatory mediators. It has also heightened interest in a continued search for new platelet inhibitors and presents new opportunities for platelet inhibitors to be used in a wide array of disease treatment strategies.