Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, the field of pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease/antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations provided compelling evidence that premature, intrapancreatic activation of digestive proteases is critical in pancreatitis onset.