Glial cells are known to respond to a variety of neural injuries and play an important role in tissue damage and repair in the injured nervous system. This glial response, which is initially characterized by the expression of proinflammatory cytokines and chemokines and the attraction of microglial cells toward sites of injury, literally occurs within seconds to minutes of the injury. This suggests that signals that are endogenous to the nervous system are responsible for initiating neuroinflammation. In this review, we summarize the most recent advances made in the identification of these endogenous signals and describe the receptors and signaling pathways by which these ligands stimulate the production of cytokines and chemokines. Among these endogenous damage signals are ligands for toll-like receptors, including several heat shock proteins and extracellular matrix components, as well as self-derived RNA and DNA and associated proteins. Growing evidence also suggests that nucleotides released upon injury and acting through P2 receptors, such as ATP and UTP or their analogues, could serve as endogenous signals for the rapid response of glial cells.