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Primary biliary cholangitis (PBC) is an autoimmune liver disease with a striking female preponderance. The mechanisms behind this predominance are still to be elucidated, although multiple theories have been postulated and investigated. Among the proposed involved factors, sex hormones have been the first to be studied, but unfortunately data have been inconclusive or conflicting. Similarly, fetal microchimerism has received a huge attention in the past, but data in PBC have been unsatisfactory especially if compared to other autoimmune diseases like systemic lupus erythematosus. Studies focused on genetic factors have generated more intriguing and robust data, reporting a few abnormalities on the X chromosome in PBC patients. However, these data are able to explain only a part of the phenotypic variability attributed to the genetic component, and most importantly, need to be validated in larger series. More recently, a novel mice model of PBC, characterised by a constitutive expression of Interferon-γ (IFN-γ), has been developed and it is notable for being the first one with female predominance. At the same time, there has been a wide interest in the role of microbiome in health and disease, as well as in epigenetics, which have tried to explain differences in biological phenotypes not covered by genetics. The aim of this review is to outline established knowledge on the topic and try to provide novel perspectives on the potential future applications of newer techniques addressing microbiome and epigenome, in order to further understand the biology of sex divergence in PBC.