Protease-activated receptors (PARs) are a class of G-protein coupled receptors (GPCRs) that play a critical role in hemostasis and thrombosis. PARs have a unique activation mechanism where the N-terminus of the receptors is proteolytically cleaved to reveal a tethered ligand that binds to the receptor and initiates signal transduction. There are four known PARs: PAR1, PAR2, PAR3, and PAR4. Each PAR is expressed by distinct genes and exhibits different physiological roles. Human platelets express PAR1 and PAR4. They are primarily activated by thrombin, a key enzyme in the coagulation cascade. Although they possess a similar activation mechanism, PAR1 and PAR4 are activated by thrombin with different kinetics and signaling outcomes. Cell signaling studies have shown that both receptors are also activated by noncanonical proteases that dictate the physiological response depending on the cellular context. Thus, PAR signaling is tightly regulated by multiple proteases to help maintain vascular integrity and hemostatic responses. Dysregulation of PAR signaling can lead to thrombosis and prolonged inflammation, making them attractive therapeutic targets. In this chapter, we explore the significance of PARs in platelet function. We provide an overview of the definition, activation mechanism, and clinical significance of PARs. This chapter details the current understanding of PAR signaling in human platelets and how this knowledge is being leveraged into developing novel antiplatelet and anti-inflammatory therapies.