Until the 1980s the role of bile acids in the initiation of liver injury in man was only suspected on the basis of the toxicity of whole bile and bile salts, and of studies showing elevations in serum and tissue levels of bile salts in liver diseases. The beneficial effects of ursodeoxycholic acid (UDCA) in primary biliary cirrhosis have provided the first firm evidence that bile acids may in some way be related to injury in man. There are many questions regarding the hepato-protective effect of UDCA that should be addressed in the near future. In particular, we do not know how chronic cholestasis induces liver fibrosis and if UDCA can prevent or counteract this process. Most cholestatic diseases have an immune pathophysiological basis. We must learn much more about the impact of cholestasis and bile acids on the immune system, particularly on endogenous or exogenous peptide presentation in cells exposed to high concentrations of bile components. We have seen that the trafficking of transporters in hepatocytes may be affected by bile acids; efforts must be made to learn more about this important issue. Finally, structural analogues of UDCA or combinations of drugs should be studied, in order to determine if better therapeutic efficacy could be obtained.