Abnormal functioning of the Cystic Fibrosis (CF) Transmembrane Conductance Regulator (CFTR) channel impairs mucociliary clearance and promotes chronic bacterial infections in the lung of CF patients. Progressive lung destruction leads to lung failure, the main cause of premature death in CF patients. However, impaired CFTR functioning affects also the pancreas and the liver with well recognized gastrointestinal manifestations that often develop early in life and contribute to the clinical deterioration. Novel therapies are under evaluation in the context of the extensive research on CF liver and gastrointestinal pathophysiology. In this review, pathological mechanisms and clinical manifestations of liver disease and pancreatic insufficiency are described with attention to future therapeutic development.