The incidence of acute pancreatitis continues to increase worldwide, and it is one of the most common gastrointestinal causes for hospital admission in the USA. In the past decade, substantial advancements have been made in our understanding of the pathophysiological mechanisms of acute pancreatitis. Studies have elucidated mechanisms of calcium-mediated acinar cell injury and death and the importance of store-operated calcium entry channels and mitochondrial permeability transition pores. The cytoprotective role of the unfolded protein response and autophagy in preventing sustained endoplasmic reticulum stress, apoptosis and necrosis has also been characterized, as has the central role of unsaturated fatty acids in causing pancreatic organ failure. Characterization of these pathways has led to the identification of potential molecular targets for future therapeutic trials. At the patient level, two classification systems have been developed to classify the severity of acute pancreatitis into prognostically meaningful groups, and several landmark clinical trials have informed management strategies in areas of nutritional support and interventions for infected pancreatic necrosis that have resulted in important changes to acute pancreatitis management paradigms. In this Review, we provide a summary of recent advances in acute pancreatitis with a special emphasis on pathophysiological mechanisms and clinical management of the disorder.