Self-reactivity and autoimmunity are processes related to the breakage of self-tolerance that can be distinguished by their different clinical outcome and are widely accepted cornerstones of immunology. The finding that several potentially autoaggressive cells contribute to the repertoire of healthy individuals has stimulated a great deal of experimental work aimed at understanding the mechanisms that prevent autoimmune pathology. In this review we will consider the basic principles, and our present knowledge of the rules that preside over the interplay of the immune system with self-components. One viewpoint stresses the importance of major histocompatibility complex (MHC) and non-MHC genes in determining genetic predisposition to develop autoimmune phenomena. At a different level there is a strong interest in understanding the mechanisms of processing and presentation of self antigens, especially during ontogeny. Another topic of major interest concerns the interaction between MHC genes and the T cell receptor (TcR) complex as well as the identification of TcR V genes that are preferentially expressed by autoimmune T cells. All of these aspects are evaluated in the context of tolerance based on deletion and anergy. Finally we will propose a general model of autoimmunity based on the most recent findings concerning the biological activity of exogenous superantigens.