Staphylococcus aureus is a robust pathogen that is capable of growing in virtually any part of the human body, and can also survive and grow in many other species. S. aureus remains the most frequent cause of hospital-acquired infection and, with the emergence and spread of drug-resistant, hypervirulent, community-acquired strains, the specter looms of the ultimate superbug. S. aureus produces an array of immune evasion factors that target various components of host immune defense. Among them are the powerful superantigen (SAg) and SAg-like (SSL) molecules, which are coded for by genes scattered across several genomic and pathogenicity islands. The SAgs universally bind MHC (major histocompatibility complex) class II and T-cell receptors to induce profound T-cell activation, while the SSLs target a range of molecules regulating opsonophagocytosis and neutrophil function. Despite functional differences, the SAgs and SSLs have clearly evolved from a single ancestral gene that now codes for a stable, two-domain protein, with each domain responsible for binding a different target molecule. This superstructure tolerates extensive surface variation, enabling a wide assortment of virulence factors targeting multiple steps in innate immunity. Notably, both the SAgs and the SSLs exhibit optimal activity for humans and non-human primates, clearly indicating that primates have been the preferred host for S. aureus evolution. This restricted function makes it difficult to assess their role in staphylococcal virulence using animal models of infection. This brief review focuses on the structural features of SAgs and SSLs and their individual functions as we currently understand them.