Protease‐activated receptors (PARs) are a family of highly conserved G protein‐coupled receptors (GPCRs) that respond to extracellular proteases via a unique proteolysis‐dependent activation mechanism. Protease‐activated receptor 1 (PAR1) was the first identified member of the receptor family and plays important roles in hemostasis, inflammation and malignancy. The biology underlying PAR1 signaling by its canonical agonist thrombin is well characterized; however, definition of the mechanistic basis of PAR1 signaling by other proteases, including matrix metalloproteases, activated protein C, plasmin, and activated factors VII and X, remains incompletely understood. In this review, we discuss emerging insights into the molecular bases for “biased” PAR1 signaling, including atypical PAR1 proteolysis, PAR1 heterodimer and coreceptor interactions, PAR1 translocation on the membrane surface, and interactions with different G‐proteins and β‐arrestins upon receptor activation. Moreover, we consider how these new insights into PAR1 signaling have acted to spur development of novel PAR1‐targeted therapeutics that act to inhibit, redirect, or fine‐tune PAR1 signaling output to treat cardiovascular and inflammatory disease. Finally, we discuss some of the key unanswered questions relating to PAR1 biology, in particular how differences in PAR1 proteolysis, signaling intermediate coupling, and engagement with coreceptors and GPCRs combine to mediate the diversity of identified PAR1 signaling outputs.