Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease characterized by the destruction of medium to large-sized bile ducts and intense, concentric fibrosis. Complications from PSC include bacterial cholangitis, cirrhosis, and cholangiocarcinoma and a therapy that might alter the natural history of the disease remains lacking. Our understanding of the pathogenesis of PSC also remains rudimentary but several theories exist, suggesting roles for genetic susceptibility, abnormal innate immune responses lymphocyte trafficking, and toxic bile formation. Medical and surgical therapies, short of liver transplantation, have been disappointing. Currently, the management of PSC is aimed largely at the endoscopic treatment of dominant biliary strictures and complications of cholestasis until the disease has progressed to cirrhosis, at which time liver transplantation is indicated. Progress in our basic understanding of PSC is desperately needed in order to rationally design new therapeutic approaches to this disease.