Protease activated receptors (PARs) are G-protein coupled receptors (GPCRs) that have a unique activation mechanism. Unlike other GPCRs that can be activated by free ligands, under physiological conditions, PARs are activated by the tethered ligand, which is a part of their N-terminus that is unmasked by proteolysis. It has been 30 years since the first member of the family, PAR1, was identified. In this review, we will discuss this unique tethered ligand mediate receptor activation of PARs in detail: how they interact with the proteases, the complex structural rearrangement of the receptors upon activation, and the termination of the signaling. We also summarize the structural studies of the PARs and how single nucleotide polymorphisms impact the receptor reactivity. Finally, we review the current strategies for inhibiting PAR function with therapeutic targets for anti-thrombosis. The focus of this review is PAR1 and PAR4 as they are the thrombin signal mediators on human platelets and therapeutics targets. We also include the structural studies of PAR2 as it informs the mechanism of action for PARs in general.