Protein A (SPA), a major cell wall component of Staphylococcus aureus, has occupied numerous investigators from its discovery in the late fifties. Its availability and avid binding to human immunoglobulins have led to extensive usage for diagnostic and research purposes. Today, SPA-based extracorporeal immunoadsorption relies on two rather different systems, namely, SPA-silica (Prosorba), and SPA-Sepharose (Immunosorba). Both systems are approved by the Food and Drug Administration for the core indications of rheumatoid arthritis and idiopathic thrombocytopenic purpura (SPA-silica) or hemophilia with inhibitors (SPA-Sepharose). Off label indications include immune disorders with a conceivable connection between autoantibody titers and disease activity, like forms of glomerulonephritis, systemic lupus erythematodes, myasthenia, and the Guillain-Barré syndrome as well as alloantibody formation in the context of e.g., transplantation. This review summarizes historical developments and important properties of SPA. Indications for extracorporeal therapy are discussed on the basis of available information and personal experience.