Studies carried out in the past 12 years have established that activation of protease-activated receptor (PAR)-1 and PAR-4 by thrombin essentially drives human platelet activation. Thrombin is the most potent physiologic agonist of platelets. PAR-1 and PAR-4 are found on human platelets and are half of the family of the four known 7-transmembrane receptors that are activated by a single proteolytic cleavage within the amino terminal extracellular domain of these receptors. This review will consider the direct and indirect evidence that apparently support the idea that PAR-1 and PAR-4 activation by thrombin drives platelet activation