Protease‐activated receptors (PARs) are widely expressed within the heart. They are activated by a myriad of proteases, including coagulation proteases. In vitro studies showed that activation of PAR‐1 and PAR‐2 on cardiomyocytes induced hypertrophy. In addition, PAR‐1 stimulation on cardiac fibroblasts induced proliferation. Genetic and pharmacologic approaches have been used to investigate the role of the different PARs in cardiac ischemia/reperfusion (I/R) injury. In mice and rats, PAR‐1 is reported to play a role in inflammation, infarct size, and remodeling after cardiac I/R injury. However, there are notable differences between the effect of a deficiency in PAR‐1 and inhibition of PAR‐1. For instance, inhibition of PAR‐1 reduced infarct size whereas there was no effect of a deficiency of PAR‐1. These differences maybe due to off‐target effects of the inhibitor or PAR‐4 compensation of PAR‐1 deficiency. Similarly, a deficiency of PAR‐2 was associated with reduced cardiac inflammation and improved heart function after I/R injury, whereas pharmacologic activation of PAR‐2 was found to be protective due to increased vasodilatation. These differences maybe due to different signaling responses induced by an endogenous protease versus an exogenous agonist peptide. Surprisingly, PAR‐4 deficiency resulted in increased cardiac injury and increased mortality after I/R injury. In contrast, a pharmacological study indicated that inhibition of PAR‐4 was cardioprotective. It is possible that the major cellular target of the PAR‐4 inhibitor is platelets, which have been shown to contribute to inflammation in the injured heart, whereas PAR‐4 signaling in cardiomyocytes may be protective. These discrepant results between genetic and pharmacological approaches indicate that further studies are needed to determine the role of different PARs in the injured heart. © 2011 IUBMB IUBMB Life, 63(6): 383–389, 2011