This article summarized several observations on the role of pancreatic secretory trypsin inhibitor in the pancreas. Although it long has been suspected that endogenous pancreatic trypsin inhibitors protect against inadvertent activation of trypsinogen, this hypothesis has gained strength from recent biochemical investigations and genetic studies of populations suffering from chronic pancreatitis. There is now considerable evidence from clinical disease associations and burgeoning experimental models that some forms of pancreatitis may be the result of an imbalance between active pancreatic proteases and their inhibitors within the pancreas. Future studies should clarify the precise molecular interactions between enzymes and inhibitors and how these may be manipulated to prevent or treat pancreatitis.