The mechanism responsible for pancreatitis, the inflammatory diseases of the pancreas, was attributed to autodigestion more than 115 years ago by Dr. Chiari.  This seemed obvious as the exocrine pancreas produces digestive enzymes capable of injuring the gland. Later, biochemical studies indicated that trypsin was the key digestive enzyme which activated the others. Therefore, trypsin became the focus if pancreatitis research and the “trypsin model” was developed. However, objective evaluation of the supports of the trypsin model indicates that most are indirect and inconclusive. The standard experimental animal models of pancreatitis cause non-specific damage, rather than specific activation of trypsinogen. The only direct support for the trypsin model comes from the observation that the trypsinogen gene is mutated in most hereditary pancreatitis.  Yet, even the hereditary pancreatitis studies are inconclusive.  Some mutations causing hereditary pancreatitis do not to alter enzymatic properties of the protease at all, but rather lead to misfolding and consequently to ER stress. Most importantly, protease inhibitors have not successfully altered the clinical course of acute pancreatitis in more than 70 clinical trials.  The most plausible explanation for the inconsistency between the popular trypsin model and clinical reality is that the animal models on which the paradigm is based are not suitable to dissect the specific role of trypsin. Recently new mouse genetic models have been developed that shed light on this area by direct manipulation of trypsin activity. The new evidence does not support trypsin as the key player but rather as just one of many mechanisms involved in initiation of the disease.  These new ideas may provide alternatives and finally some clinically useful approaches for this disease.