Heparan sulfate proteoglycan, a component of endothelial cell membranes and extracellular matrices, is involved in a number of the critical functions of endothelium and of antigen-presenting cells. This review discusses how heparan sulfate is released from endothelial cells during inflammation, how to loss of heparan sulfate potentially alters endothelial cell physiology, and how the presence of heparan sulfate in a soluble form might regulate the functioning of lymphocytes at sites of inflammation.