Understanding of the mechanisms for the development of sepsis during acute pancreatitis has increased greatly over the last 5 years. It has become clear that the gut serves as a source of bacteria in a variety of animal models of acute pancreatitis. Bacterial translocation from the intestinal lumen to extraintestinal sites including pancreatic necrosis may occur via the lymphatic, hematogenous or direct transperitoneal route. Increased mucosal permeability, reduced bowel motility, and an impaired host defense have been identified as possible causes for translocation. Standard prophylactic management for the prevention of sepsis in acute pancreatitis includes the use of systemic broad-spectrum antibiotics with optimal penetration into the pancreas, such as imipenem. However, selective gut decontamination clearly reduces the incidence of pancreatic infection in animal models and, probably, in humans, too.