Autoimmune diseases such as insulin-dependent diabetes mellitus, rheumatoid arthritis, and multiple sclerosis are common in the western world and are often devastating diseases which pose serious health problems. The key feature of such diseases is the development and persistence of inflammatory processes in the apparent absence of pathogens, leading to chronic breakdown of selected tissues. To date, no comprehensive explanation can be given for the onset or persistence of autoimmunity. As a rule, the chronic activation of helper T lymphocytes reactive against self proteins appears to be crucial for fueling the destructive autoimmune process, but why this occurs remains to be established. In this review, we present an overview on the rules that govern activation of T lymphocytes and on the factors that control it. The contribution of both genetic and environmental factors are discussed, clarifying that most autoimmune disease are of multifactorial origin. Special emphasis is given to the contribution of infectious events and the role of stress proteins in the process. In attempts to dissect the mechanisms involved in autoimmunity and to develop ways of blocking disease, experimental animal models are widely employed. We describe the various experimental models that exist for the study of multiple sclerosis, diabetes, and other autoimmune diseases and on the experience that has been gained in such models with experimental therapies to block the activation of self-reactive T lymphocytes. The lessons that can be drawn from these studies provide hope that continued efforts will lead to the successful development of antigen-specific strategies which block the development of autoimmunity also in humans.