Ischaemia/reperfusion (I/R) injury is central to a number of pathologies including myocardial infarction and stroke. Several cellular processes are involved in the progress of I/R injury, involving complex interactions between coagulation and inflammatory or apoptotic processes. Besides for their anti-coagulant function, anticoagulant proteins such as activated protein C (APC), active site inhibited factor VIIa (ASIS), tissue factor pathway inhibitor (TFPI), and antithrombin (AT) are also known for their anti-inflammatory or cell protective effects. This review gives an overview of the application of these anti-coagulants in several animal models of I/R injury in critical organs and describes the effects of these proteins on cellular processes including inflammation and apoptosis. The future testing of mutant forms of some of these inhibitors including APC in a clinical setting should be actively explored.