Acute pancreatitis begins as acute pancreatic injury and may generate a systemic inflammatory response that evolves into multiorgan failure, leading to death. Multiple inciting factors such as toxins (alcohol), gallstones, or endoscopic retrograde cholangiopancreatography result in a cascade of events beginning with the intra-acinar activation of zymogens and the release of cytokines and other proinflammatory mediators. Their release is a major determinant of the systemic inflammatory response and distant organ failure. Attempts to attenuate the severity of acute pancreatitis by blocking specific inflammatory mediators have had limited success. This review is divided into experimental acute pancreatitis and clinical acute pancreatitis. The distinction is maintained because although animal models of disease have helped define the pathogenesis of acute pancreatitis, they do not completely reproduce the clinical syndrome of human acute pancreatitis or guarantee equal success of therapies in humans.