The pathophysiologic concept of acute pancreatitis focuses on early events inside acinar cells such as activation of trypsin. Despite significant progress in the understanding of molecular events in experimental pancreatitis, knowledge of these mechanisms has not yet been translated into therapeutic strategies useful in humans. A single morphologic or laboratory marker reliably predicting the individual course of acute pancreatitis still awaits discovery. The clinical outcome of acute pancreatitis is dependent on the presence of necrosis and systemic complications. The extent of the systemic inflammatory response to local pancreatitis seems to be the rate-limiting step. Several mechanisms shed light on the interconnectivity between intra-acinar protease activation and immunoregulatory processes. Deciphering these cell biologic connections has already had an impact on the clinical management of patients and the identification of prognostic markers in human disease. However, further investigations of pancreatic pathophysiology are needed to initiate novel therapeutic strategies.