Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by fibro-obliterative inflammation of the entire biliary tree. It is a slowly progressive disease with an undulating course, resulting in terminal biliary cirrhosis after a median period of about 12 years after diagnosis. The etiology of the disease is unknown and there is no effective therapy that can halt disease progression. Around 8% of PSC patients develop cholangiocarcinoma, which, by the time it is diagnosed, cannot be treated curatively. The purpose of this article is to review the current knowledge about primary sclerosing cholangitis and to speculate on future strategies to address the issues of etiology and therapy.