Animal models of autoimmunity fall into four categories: (1) those induced by immunization with self-antigen, (2) those induced by exogenous agents including drugs, biologicals, environmental agents, and microbes, (3) those that arise spontaneously, and (4) those that are produced by genetic manipulation (homologous recombination, transgenics). The autoimmunity exhibited by these models covers a spectrum of diseases that fall into two broad categories: organ-specific and systemic autoimmunity. In organ-specific autoimmunity the target antigens and pathology are found in a single organ. Examples include myasthenia gravis, gastritis, thyroiditis, and diabetes. In systemic autoimmunity the self-antigens are far more ubiquitous in their tissue distribution and pathology is manifest in multiple organ systems. Examples include arthritis, systemic lupus erythematosus (SLE), and scleroderma. Autoimmunity is multifactorial in nature with genetic predisposition, environment, infection, and chemical/drug exposures influencing disease expression. The overarching theme in controlling the expression of autoimmunity is the maintenance of immune tolerance to self. Animal models of autoimmune diseases have played a central role in the discovery of many of the mechanisms that result in the breaking of self-tolerance. This chapter describes a number of experimental animal models of autoimmunity and the underlying mechanisms that lead to disease. Also discussed is the influence of chemical/drug exposure in the generation of autoimmunity and the use of animal models as both healthy and autoimmune-prone populations in identifying potential chemical inducers of autoimmunity.