Staphylococcus aureus strains that cause human diseases produce a large family of pyrogenic toxin superantigens (SAgs). These include toxic shock syndrome toxin-1 (TSST-1), the staphylococcal enterotoxins (SEs), and the SE-like proteins; to date, 23 staphylococcal SAgs have been described. Among the SAgs, three have been highly associated with human diseases (TSST-1, SEB, and SEC), likely because they are produced in high concentrations compared to other SAgs. Another major family of exotoxins produced by S. aureus is the cytolysins, particularly α-, β-, γ-, and δ-toxins, phenol soluble modulins, and leukocidins. This review discusses the association of SAgs with human diseases and particularly the “outside-in” signaling mechanism that leads to SAg-associated diseases. We discuss SAg interactions with three host immune cell receptors, including variable regions of the β-chain of the T cell receptor, MHC II α- and/or β-chains, and an epithelial/endothelial cell receptor that may include CD40. To a lesser extent, we discuss the role of cytolysins in facilitating disease production by SAgs.