Primary sclerosing cholangitis (PSC) is a rare and complex chronic cholestatic liver disease, and its management is hindered by a very poor understanding of its pathogenesis. Endogenous bile acids are likely to play a role either directly or indirectly in the pathogenesis and/or progression of PSC (‘toxic-bile’hypothesis). At present, no medical therapies have been proven to delay disease progression. Ursodeoxycholic acid (UDCA) is the agent that has received the most attention. Based on large randomized studies, it appears that UDCA at doses from 13 to 23mg/kg/d has no proven benefit on survival, but is well tolerated and improves serum liver tests and surrogate markers of prognosis whereas, at higher doses (28–30mg/kg/d), it is associated with a worsened outcome. However, except at very high doses and despite the controversies, many hepatologists still consider UDCA a reasonable treatment choice. Indeed, its use at dosages of 15–20mg/kg/d has recently been approved for the treatment of PSC by the French National Health Authority. In addition, 24-nor-ursodeoxycholic acid, a side-chain-modified UDCA derivative, has shown promising results in animal models of PSC and is currently under investigation in humans.