The idea that pancreatitis—a common, painful, and life-threatening disease1,2—is caused by the pancreas digesting itself is about 130 years old,3 and the foremost villain in this process is believed to be trypsin, a serine protease discovered even earlier. The problem is that exocrine pancreatic (acinar) cells synthesize not trypsin per se, but trypsinogen, its inactive precursor (zymogen). In normal physiology, trypsinogen is converted to trypsin (activated) only in the duodenum after being secreted in response to a meal.