The NF-kappa B family of transcription factors are associated with the regulation of innate and adaptive immunity to infection. Infection of C57BL/6 mice with Toxoplasma gondii resulted in up-regulation of NF-kappa B activity that included the NF-kappa B family member RelB. To assess the role of RelB in the regulation of the immune response to this infection, we challenged RelB-deficient mice (RelB-/-) and wild-type (WT) littermate controls with T. gondii. Although WT controls were resistant to T. gondii, RelB-/- mice succumbed 10-15 days after infection. Examination of accessory cell functions associated with resistance to T. gondii revealed that RelB-/- macrophages stimulated with IFN-gamma plus LPS or TNF-alpha produced IL-12 as well as reactive nitrogen intermediates and inhibited parasite replication similar to WT macrophages. Analysis of the systemic responses of RelB-/- and WT mice revealed that infected mice had similar serum levels of IL-12. However, RelB-/- mice challenged with T. gondii produced negligible levels of IFN-gamma and had reduced NK cell activity compared with WT mice. Similarly, splenocytes from uninfected RelB-/- mice stimulated with polyclonal stimuli were deficient in their ability to produce IFN-gamma. Together, our results demonstrate that RelB is essential for the development of innate NK and adaptive T cell responses that lead to the production of IFN-gamma and resistance to T. gondii.