The article focuses on three potential mechanisms by which cystic fibrosis (CF) may lead to exocrine pancreatic dysfunction. Although not all-inclusive, the hypotheses presented provide a framework through which defects in the CF gene product, CFTR (cystic fibrosis transmembrane conductance regulator), may lead to pancreatic exocrine dysfunction. Three potential mechanisms include (1) obstruction of pancreatic ducts by inspissated plugs, (2) inhibition of endocytosis in acinar cells, and (3) imbalance in membrane lipids in CF-regulated cells. Any of these abnormalities alone or in combination would explain the development of pancreatic exocrine insufficiency.