Progressive intrahepatic cholestasis (PIHC, also known as progressive familial intrahepatic cholestasis) is a general term encompassing a devastating group of illnesses manifest by severe morbidity and potential mortality. By definition these diseases are characterized by persistent cholestasis that is the result of intra-hepatic rather than extra-hepatic pathology. Recent scientific advances have begun to clarify the molecular basis of many of these disorders. The morbidities of these diseases are primarily the result of profound cholestasis. This cholestasis is often associated with intractable pruritus, which leads to a very poor quality of life. Normal development and sleep are not possible for the affected individual and family dynamics are sometimes irreparably damaged. The cholestasis also leads to complications of fat soluble vitamin malabsorption including osteopenia and pathologic bone fractures, xeropthalmia, and peripheral neuropathy. End-stage liver disease and all of its attendant problems may develop in affected individuals by young adulthood. Optimal therapeutic approaches to PIHC are not well established and disease-specific approaches may be required.