The production of IFN-γ by T cells and the ability of this cytokine to activate the transcription factor STAT1 are implicated in the activation of antimicrobial mechanisms required for resistance to intracellular pathogens. In addition, recent studies have suggested that the ability of STAT1 to inhibit the activation of STAT4 prevents the development of Th1 responses. However, other studies suggest that STAT1 is required to enhance the expression of T-bet, a transcription factor that promotes Th1 responses. To address the role of STAT1 in resistance to T. gondii, Stat1−/− mice were infected with this pathogen, and their response to infection was assessed. Although Stat1−/− mice produced normal serum levels of IL-12 and IFN-γ, these mice were unable to control parasite replication and rapidly succumbed to this infection. Susceptibility to toxoplasmosis was associated with an inability to up-regulate MHC expression on macrophages, defects in NO production, and the inability to up-regulate some of the IFN-inducible GTPase family of proteins, molecules associated with antitoxoplasma activity. Analysis of T cell responses revealed that STAT1 was not required for the development of a Th1 response, but was required for the infection-induced up-regulation of T-bet. Together these studies suggest that during toxoplasmosis the major role of STAT1 is not in the development of protective T cell responses, but, rather, STAT1 is important in the development of antimicrobial effector mechanisms.