The pathways leading to autoimmunity remain enigmatic despite numerous lines of experimental inquiry and epidemiological evidence. The mechanisms leading to the initiation and perpetuation of specific diseases such as primary biliary cirrhosis (PBC) or multiple sclerosis (MS) remain largely enigmatic, although it is established that a combination of genetic predisposition and environmental stimulation is required. The growing number of genome-wide association studies and the largely incomplete concordance for autoimmune diseases in monozygotic twins concur to support the role of the environment (including infectious agents and chemicals) in the breakdown of tolerance leading to autoimmunity through different mechanisms. In the present article we illustrate the current hypotheses related to an environmental impact on the onset of PBC and MS as two representative conditions investigated with complementary approaches. Indeed, while a role of post-translational antigen modifications has been proposed for MS, this field remain unexplored in PBC where, conversely, most evidence is gathered from geoepidemiology and experimental data on xenobiotics or infectious agents.