The endothelial cell protein C receptor (EPCR) plays a critical role in augmenting protein C activation by the thrombin-thrombomodulin complex and in modulating the functions of the protein C pathway to aid in preventing organ damage due to various challenges. EPCR exhibits a sequence and three-dimensional homology with the major histocompatibility class 1/CD1 family of proteins. This family of proteins is characterized by having a deep groove that is usually used in antigen presentation. In the case of CD1c and CD1d, this groove is filled with a lipid antigen, usually a glycolipid. Like the CD1 series, EPCR has a lipid in the corresponding groove. In this case, the lipid is usually phosphatidylcholine, but it may be phosphatidylethanolamine. The bound lipid contributes to protein C binding, but its structure suggests a role in maintaining EPCR structure rather than contributing directly to protein C binding. Potential roles for EPCR in hematopoiesis are suggested by the finding that EPCR is located on hematopoietic stem cells at reasonably high concentrations. The structure and the lipid antigen suggest that EPCR may be involved in preventing autoimmunity, which would be consistent with findings in CD1d knockout mice. Complete deletion of EPCR function results in embryonic death, at least in part due to placental thrombosis. In adult animals, the anticoagulant and anti-inflammatory responses to endotoxin increase with increasing EPCR expression. Some of the anti-inflammatory activity is likely to be due to EPCR's interactions with the integrin Mac-1 (CD11b/CD18) on leukocytes, an interaction that probably limits tight adhesion of leukocytes to activated endothelium. Thus, available data suggest a potential role of EPCR in hematopoiesis, autoimmunity, and the control of both the coagulation and inflammation responses to infection and trauma.