Primary biliary cirrhosis (PBC) is a chronic, autoimmune, cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis of the liver and may need liver transplantation in the late stage of disease. Fatigue and pruritus are the most common symptoms of PBC, but the majority of patients are asymptomatic at first presentation. There is no specific treatment for fatigue in PBC, but modafinil has shown some potential beneficial effects, such as increased energy levels and decreased total sleep time. This Review article discusses the natural history and the measurement of fatigue in patients with PBC. The central and the peripheral mechanisms that have been suggested for the pathogenesis of fatigue in PBC are also discussed and treatment options are reviewed.