Because of their ability to become rapidly activated at places of vascular injury, platelets are important players in primary hemostasis as well as in arterial thrombosis. In addition, they are also involved in chronic pathological processes including the atherosclerotic remodeling of the vascular system. Although primary adhesion of platelets to the vessel wall is largely independent of G protein-mediated signaling, the subsequent recruitment of additional platelets into a growing platelet thrombus requires mediators such as ADP, thromboxane A(2), or thrombin, which act through G protein-coupled receptors. Platelet activation via G protein-coupled receptors involves 3 major G protein-mediated signaling pathways that are initiated by the activation of the G proteins G(q), G(13), and G(i). This review summarizes recent progress in understanding the mechanisms underlying platelet activation and thrombus extension via G protein-mediated signaling pathways.