There are several examples of liver tolerance: the relative ease by which liver allografts are accepted and the exploitation of the hepatic microenvironment by the malarial parasite and hepatotrophic viruses are notable examples. The vasculature of the liver supports a unique population of antigen presenting cells specialised to maintain immunological tolerance despite continuous exposure to gut-derived antigens. Liver sinusoidal endothelial cells and Kupffer cells appear to be key to the maintenance of immune tolerance, by promoting T cell anergy or deletion and the generation of regulatory cell subsets. Despite this, there are three liver diseases with likely autoimmune involvement: primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. How can we reconcile this with the inherent tolerogenicity of the liver? Genetic studies have uncovered several associations with genes involved in the activation of the innate and adaptive immune systems. There is also evidence pointing to pathogenic and xenobiotic triggers of autoimmune liver disease. Coupled to this, impaired immunoregulatory mechanisms potentially play a permissive role, allowing the autoimmune response to proceed.