Superantigens (SAgs) activate the immune system by stimulating massive proliferation of T cells in a major histocompatibility complex (MHC)-dependent manner. This excessive increase in T cells results in the release of cytokines such as interleukin-2 (IL-2), interferon-gamma (IFNγ), and tumor necrosis factor-alpha (TNFα). As an adaptive feedback mechanism, SAgs can also activate the hypothalamic pituitary adrenal (HPA) axis by stimulating the release of corticotropin releasing hormone (CRH) from the hypothalamus, adrenocorticotropic hormone (ACTH) from the anterior pituitary, and ultimately corticosterone (CORT) from the adrenal gland. Additionally, SAg exposure modifies behavior, although it has not been shown to induce malaise or decrease mobility. Some behavioral consequences include increased gustatory neophobia, neophobia to inanimate non-gustatory objects, and heightened anxiety. Cytokines such as TNFα have been shown to mediate some of these behavioral consequences as well as the endocrine and neurobiological effects of SAg exposure. The particular behavioral repertoire and cytokine profiles observed are in some cases unique to SAgs, as compared to other immune challenges such as lipopolysaccharide (LPS). Therefore, SAgs serve as a useful model to understand the behavioral, endocrine, and neurobiological effects of a T cell driven immune response.