Family studies suggest that genetic factors play a role in determining susceptibility to primary biliary cirrhosis (PBC). A number of polymorphic genes with small and additive effects may thus encode factors predisposing to this 'polygenic' disease. All the published data on genetic predisposition to PBC have been obtained from association studies, based on comparison of the frequency of an allele in unrelated affected and unaffected individuals from a population; however, many studies have examined only small datasets. There is evidence from several different populations to support a role for the major histocompatibility complex (MHC) class II antigen, HLA DR8, in increased risk of PBC. Other 'candidate' genes, selected on the basis of postulated mechanisms of breakdown of self-tolerance, are now beginning to be tested in association studies, including cytokines and immunomodulatory molecules. These studies and other approaches to identifying genes that confer susceptibility to an autoimmune disorder, exemplified by PBC, are discussed.