Autoimmune diseases, which comprise over 80 clinically distinct conditions, are characterized by the presence of autoantibodies or autoreactive T cells directed against self structures (autoantigens). While these often incurable disorders appear to be rapidly increasing in recognition throughout the world, their rarity, heterogeneity and complex etiologies have limited our understanding of their pathogeneses. The precise mechanisms for the development of autoimmune diseases are not known, however, evidence from many complementary lines of investigation suggests that autoimmune diseases result from the interactions of both environmental and genetic risk factors. While considerable progress has been made in understanding multiple genetic risk factors for many autoimmune diseases, relatively little information is now available regarding the role of the environment in the development of these illnesses. This chapter examines the limited but growing evidence for the role of the environment in the development and progression of autoimmune diseases, the specific exposures that have been suspected of being involved, the possible mechanisms by which these agents may induce and sustain autoimmune processes and the approaches needed to better understand these issues in the future. Identifying the necessary and sufficient genetic and environmental risk factors for disease holds the promise of allowing for the prevention of some illnesses through avoidance of environmental risk factors by genetically susceptible individuals or via gene or other therapies to correct the effects of deleterious genetic risk factors in the case of unavoidable environmental agents.