Whether or not T cell receptor engagement leads to full activation or tolerance is determined by the context in which the antigen is encountered. Antigen presented by activated APCs in the presence of costimulation leads to full T cell activation, while antigen presented by resting APCs leads to tolerance. Pathogen-associated molecular patterns in the form of toll-like receptor ligands play a critical role in activating APCs and promoting T cell activation. In this review we hypothesize that low-molecular-weight species of the extracellular matrix polymer hyaluronan also performs this function by acting as an endogenous danger signal.