The ability of many microbial and inflammatory stimuli to activate members of the Rel/NF-κB family of transcription factors is associated with the regulation of innate and adaptive responses required to control infection. Individual family members play distinct roles during different infectious and inflammatory responses. For example, c-Rel is essential for the production of IL-12 in response to LPS, but dispensable for IL-12 production in response to Toxoplasma Ag. To assess the role of c-Rel during immunity to the intracellular pathogen Toxoplasma gondii, wild-type (WT) and c-Rel−/− mice were infected with Toxoplasma and the immune response was analyzed. c-Rel−/− mice developed severe toxoplasmic encephalitis with increased numbers of parasites compared with WT controls and succumbed to infection within 5–8 wk. Although increased susceptibility of c-Rel−/− mice was associated with decreased T cell activation, proliferation, and production of IFN-γ, these mice were able to generate Th1 effector cells that were present in the brain during chronic infection. In vitro mixing studies using WT and c-Rel−/− dendritic cells and WT and c-Rel−/− TCR transgenic T cells indicated that c-Rel−/− dendritic cells are defective in their ability to stimulate T cell responses. However, when c-Rel−/− T cells were transferred into T cell-deficient hosts, early defects in T cell activation, proliferation, and IFN-γ production persisted, and these mice remained susceptible to infection. Together, these studies indicate that although c-Rel is an important regulator of innate immune responses, it also plays an important role in optimization and maintenance of adaptive T cell responses during infection.