Cystic fibrosis (CF) is the most common potentially lethal genetic disease in the Caucasian population. The disease results from mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl(-) channel in the apical membrane of most secretory epithelia. In the liver, CFTR is located in biliary epithelial cells or cholangiocytes and gallbladder epithelia, where it appears to play a role in normal bile formation. However, how a defective CFTR protein leads to associated liver and biliary disease in a subset of patients with CF is unknown. Improvements in life expectancy have led to an increasing recognition of hepatobiliary complications from CF. Whereas the biliary tract disease is usually clinically evident, the liver involvement may progress silently, only manifesting as end-stage liver disease and portal hypertension. Unlike the pancreatic involvement in CF, a genotype-phenotype correlation is not apparent in the expression of liver disease, suggesting the presence of as yet unidentifiable "genetic modifiers" influencing disease expression. This review focuses on the pathogenesis, clinical manifestations, screening, diagnosis, and treatment of CF hepatobiliary disease.