Cystic fibrosis (CF) is a genetic disorder characterized by epithelial electrolyte transport abnormalities, elevated sweat Cl– concentrations, pancreatic insufficiency, and chronic lung disease in most patients. It is the most common potentially fatal genetic disorder in the Caucasian population, affecting 1 in 2,400–3,500 live births [1, 2]. It is an autosomal recessive disorder caused by a mutation in the gene CFTR encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane channel protein. The clinical significance of hepatobiliary disease in CF has not been well characterized primarily because of two factors: (1) pulmonary involvement leads to early mortality in a majority of patients, and (2) the clinical identification of CF-associated liver disease has been difficult because, although it is progressive, liver involvement is often asymptomatic until the appearance of end-stage complications. Recently, with improved pulmonary treatments, median life expectancy now exceeds 40 years and CF-associated hepatobiliary disease is recognized and characterized more comprehensively. Liver disease is now the third major cause of death in CF (after pulmonary disease and complications of lung transplant). In recent years, advances in our understanding of the function of CFTR in bile duct epithelia have provided a stronger scientific basis for the pathogenesis of the disease, leading to insights concerning potentially novel therapeutic approaches.