Acute pancreatitis is associated with significant morbidity and a mortality rate of approximately 8%. In severe pancreatitis, necrosis at the site of inflammation and remote organ failure develop in the course of disease. Pancreatic injury is initiated by molecular events in acinar cells. Premature activation of digestive enzymes, disturbances of intracellular calcium, and activation of transcription factors such as NF-kappaB characterize the initial phase of acute pancreatitis. The release of proinflammatory mediators and the recruitment of immune cells expand the local disturbances to a systemic inflammatory response associated with failure of distant organs such as lungs or kidney. The use of transgenic or knockout mice together with classic models of secretagogue-induced pancreatitis has provided considerable insight into the role of individual cellular or humoral factors in different stages of experimental pancreatitis. Transfer of these findings into clinical management or novel therapeutic strategies so far has had only very limited success. This may be due to the limitation of pancreatitis models to mimic completely the human disease. Therefore, a distinction between experimental models and clinical acute pancreatitis has to be maintained. The first part of this review will therefore concentrate on the initiation of acinar cell injury in experimental pancreatitis. Novel insights covering the mechanism by which local pancreatic involvement expands into systemic inflammation described in the second part. Progress in the clinical management and treatment of acute pancreatitis in humans is the focus of the third part of this review.