There has been impressive progress in unraveling pathogenetic factors of PBC over the past decade. In favor of a genetic background, an outstanding concordance rate among monozygotic twins has been identified, as well as various genetic associations. Clustering of distinct HLA alleles and, among others, allelic variations of TNFα, CTLA-4, and anion exchanger 2 (AE2), respectively, have been described. In addition, there is compelling evidence for an environmental factor required for the development of PBC. Xenobiotics capable of modulating mammalian proteins to form neoantigens have been shown to induce pathologies resembling PBC in animal models. Furthermore, various infectious agents have been associated with PBC in humans, although direct experimental evidence for their role in the pathogenesis is limited. Lastly, disruption of AE2 [204] and genes involved in the regulation of immune response, such as the TGF-β II or IL-2 receptor or the AE2, gives rise to histologic and serologic changes mimicking PBC in different animal models and may be contributing to susceptibility for PBC in human.