Tissue plasminogen activator has been well characterized as a serine protease that functions in control of blood clotting by releasing the protease plasmin from the inactive zymogen plasminogen. Now evidence is accumulating that indicates that tPA may actually have broader roles. Fredriksson et al. searched for the protease responsible for activation of platelet-derived growth factor C (PDGF-C). Cleavage of an N-terminal CUB (complement-binding) domain is required to activate PDGF-CC dimers and allow PDGFC to stimulate the PDGF receptor α. Such activation of PDGF-CC was promoted by media from cells expressing tPA. Cells from knockout animals lacking tPA failed to activate PDGF-CC and showed inhibited growth. This study and others that implicate roles for tPA in modifying the NMDA receptor and activating brain-derived neurotophic factor suggest that clotting is not the only process regulated by tPa.