Superantigens (SAgs) are derived from diverse sources, including bacteria, viruses, and human hepatic tissue. SAgs initially cause lymphocyte activation but then result in clonal deletion and anergy, leading to immune tolerance. They can also act as superallergens by stimulating a broad spectrum of mast cells and basophils in patients with allergic conditions. The newly described staphylococcal SAg-like proteins subvert innate immune function by several mechanisms, which are distinct from SAgs’ effects on lymphocytes and other acquired immune processes. There is mounting evidence to suggest that SAgs play a role in the pathophysiology of inflammatory airway disease. The pathophysiologic role of SAg-like proteins awaits clarification.