Publisher Summary This chapter discusses the roots of and routes to autoimmunity. Ehrlich developed the first general theoretical concept of specific immunity and natural self-tolerance. His side-chain receptor theory, with its striking similarities to the current selection theory of acquired immunity, proposed that cells involved in immune responses produced sessile “side-chain” receptors that were initially anchored to the cell. The attachment of an antigenic molecule to a receptor stimulates the formation by the cell of new receptors, and there is production of the same receptors by additional cells in the body, “activated cells” and “memory cells” in later usage. The production of a surplus of receptors resulted in these being shed as free particles—antibodies—that bind antigen in the circulation. Autoimmune Diseases was published as a theoretical and clinical science description of autoimmunity and disease. The theoretical basis comprised Burnet's clonal selection theory of acquired immunity that includes deletion in embryonic life of any potential self-reactive immunocytes.