In recent years, a number of articles have been published on the treatment of acute pancreatitis in experimental models and most of them concerned animals with mild disease. However, it is difficult to translate these results into clinical practice. For example, infliximab, a monoclonal TNF antibody, was experimentally tested in rats and it was found to significantly reduce the pathologic score and serum amylase activity and also to alleviate alveolar edema and acute respiratory distress syndrome; however, no studies are available in clinical human acute pancreatitis. Another substance, such as interleukin 10, was efficacious in decreasing the severity and mortality of lethal pancreatitis in rats, but seems to have no effect on human severe acute pancreatitis. Thus, the main problem in acute pancreatitis, especially in the severe form of the disease, is the difficulty of planning clinical studies capable of giving reliable statistically significant answers regarding the benefits of the various proposed therapeutic agents previously tested in experimental settings. According to the pathophysiology of acute pancreatitis, the efficacy of the drugs already available, such as gabexate mesilate, lexipafant and somatostatin should be re-evaluated and should be probably administered in a different manner. Of course, also in this case, we need adequate studies to test this hypothesis.