Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and, ultimately, the need for liver transplantation. The pathogenesis of PSC is poorly understood, and due to lack of effective medical therapy, PSC remains a leading indication for liver transplantation in nNorthern Europe and the USA, despite the relatively low prevalence (1/10,000). Affected individuals are diagnosed at a median age of 30-40 years and suffer from an increased frequency of IBD (60-80%) and autoimmune diseases (25%). A considerable proportion of the patients (10–20%) develops cholangiocarcinoma. Conversely, approximately only 5% of patients with IBD develop PSC. A 9 to 39-fold sibling relative risk indicates a strong genetic component to PSC risk. In addition to multiple strong associations within the Human Leucocyte Antigen (HLA) complex, recent association studies have identified 15 genome-wide significant loci. The strong HLA associations and clinical co-occurrence of immune-mediated diseases suggest that autoimmunity plays a role.