The vast majority of patients with acute pancreatitis either have gallstones or drink too much alcohol. While little is known about the action of ethanol on the exocrine pancreas, the mechanisms involved in gallstone-induced pancreatitis have recently been elucidated to an extent that allows conclusions about the pathophysiology of pancreatitis. In the following review article we will discuss the clinical and experimental studies which have shaped our understanding of biliary pancreatitis. While most of the questions regarding the association of gallstones and pancreatitis appear to be resolved, the intracellular alterations which immediately follow these triggering events and ultimately lead to acinar cell necrosis are less well understood. These early pathophysiological changes within the pancreas have been the target of an intense research interest and the subject of sometimes equally passionate controversies. We will discuss the studies that have addressed the premature and intracellular activation of digestive enzymes in acute pancreatitis and review some of the current theories and arguments which attempt to confront this issue.