Acute pancreatitis is frequently a mild disease. However, about one in every five patients develops a more severe disease with (peri)pancreatic necrosis. Intestinal bacterial translocation is generally accepted as the main source of infection of pancreatic necrosis. Since antibiotic prophylaxis has failed to provide any benefit in acute necrotizing pancreatitis and because it is definitely not recommended in clinical practice, avoiding intestinal bacterial translocation is the main aim in the prevention of infection of pancreatic necrosis. The presence of fever early in acute pancreatitis is usually secondary to the release of inflammatory mediators. Later, the development of clinical and laboratory markers of sepsis in the absence of any extrapancreatic infection is the basis for the diagnosis of infected pancreatic necrosis. Infected pancreatic necrosis is currently managed following a minimally invasive step-up approach. This approach is based on the stepwise use of systemic antibiotics, endoscopic or percutaneous drainage, and endoscopic or percutaneous minimally invasive necrosectomy.