PAR1, member of the family of protease-activated receptors, is a GPCR whose activation requires a proteolytic cleavage at its extracellular N-terminus to unveil a tethered activating ligand. Although thrombin is the main activator of this receptor, diverse other proteases can also activate and disarm PAR1. Besides, tethered activating ligand-based peptides (PAR-APs) can also activate the receptor. PAR1 mainly signals via G proteins but, it can also signal using β-arrestin pathways and by transactivation of other receptors. This complex PAR1 interactome is completed with the receptor desensitization, trafficking, and degradation. PAR1 has shown species-, cellular-, and physiological or pathological state-dependent specificity. This review try to give an overview on the complex PAR1 interactome, its therapeutic impact upon the cardiovascular, immune and nervous systems, inflammation and cancer, as well as, on its modulation with agonists and antagonists.