Acute pancreatitis (AP) is the most common gastrointestinal disorder requiring hospitalization, with a high rate of morbidity and mortality. Severe AP is characterized by the presence of persistent organ failure involving single or multiple organs. Clinical evolution, laboratory and radiological assessment are necessary to evaluate the prognosis and inform the management of AP. The onset of severe AP may be classified in two principal phases. The early phase, during the first week, is characterized by the activation of the auto-inflammatory cascade, gut dysbiosis, bacterial translocation, and the down-regulation of immune responses. The late phase is characterized by the development of local and systemic complications. Several old paradigms have been amended in the management of AP patients, such as the indication of nutrition, the use of antibiotic therapy, pain control strategies, and even the use of surgery. Real world evidence has shown that in the majority of cases a step-up approach is most effective. In this review, we discuss the clinical assessment and improvements to the management of patients with severe AP in a high volume center where a multi-disciplinary approach is performed.