While glial cells are recognized for their roles in maintaining neuronal function, there is growing appreciation of the ability of resident glial cells to initiate and/or augment inflammation following trauma or infection in the central nervous system (CNS). The tachykinin, substance P, is found throughout the CNS, with evidence for both neuronal and glial cells as being sources of this neuropeptide. Substance P is well known to augment inflammatory responses at peripheral sites, such as the gastrointestinal tract and skin, which raises the possibility that this tachykinin might serve a similar function within the brain. This review focuses on the evidence for tachykinins in regulating the immune functions of CNS glial cells. Neurokinin-1 (NK-1) receptors have a high affinity for substance P and are expressed by a number of resident CNS cell types, including astrocytes and microglia. Importantly, substance P/NK-1 receptor interactions elicit activation of signal transduction pathways in both cell types and can initiate, or augment, inflammatory responses by astrocytes and microglia. The ability of substance P to augment immune responses of glial cells has important ramifications for the development of protective host responses within the CNS or, alternatively, the progression of damaging inflammation.