The etiologic origins of autoimmune disease remain an enigma. Although considerable information on the mechanisms of immunopathology has been acquired, in part from murine models, such mechanisms have yet to be substantiated in human autoimmune disease. This absence of validation is especially true for organ-specific diseases like those affecting the liver. In this review we focus on the putative role of xenobiotics as inducing agents for autoimmune liver pathology. In particular, we discuss the autoantibody immune response, the humoral hallmark of autoimmune disease, as well as cellular immune responses. We believe that exposure to environmental factors, namely xenobiotics, is the initiating straw that breaks the camel's back, leading to the loss of tolerance to self proteins in genetically susceptible hosts. The end result is a perpetuating process that is determined by the governing features of the genetics of the host and by exposure to the inciting environmental agent. Interestingly, the liver, an organ that plays a major role in immune tolerance, can itself become the target of autoreactivity and immune destruction.