Pancreatitis remains an intractable disease because no causative treatment is yet available. Recent studies have uncovered some of its underlying pathophysiology, a requirement for identifying potential treatment targets. These advancements were achieved by human genetic studies and by introducing genetic mechanisms into experimental pancreatitis models.Cationic trypsin mutations are the most prominent genetic risk factor for pancreatitis. Investigators have now introduced genetically modified trypsin variants into transgenic animals. In this manner they characterized the role of cellular defense mechanisms, for example degradation of active trypsin by chymotrypsin-C, but also found that increased autoactivation or decreased degradation, not only boost disease severity but also drive progression to chonic pancreatitis. Other studies found that harmful trypsin effects are not restricted to acinar cells, that other digestive enzymes, notably pancreatic elastase, can also induce cellular injury and that endoplasmic-reticulum-stress is an important mechanism when mutations induce protein misfolding.Identifying genetic subsceptibility factors for a disease never completely uncovers its underlying pathogenesis or potential treatment targets. This requires studying the mechanisms suggested by genetic findings in experimentel disease models. Pancreatitis is a field, in which much progress has now been achieved by adopting this approach.