The explosive expansion of our knowledge of the basic properties of the mammalian proteolytic enzymes has stimulated a parallel growth in their applications to clinical medicine. The outcome of this research has been significant advances in the therapy, diagnosis, and pathogenesis of disease processes in almost all fields of medicine. The enzymes discussed in this paper are pepsin, the pancreatic endopeptidases (chymotTypsin, trypsin, kallikrein, and elastase), the blood proteolytic enzymes (thrombin and plasmin), the pancreatic exopeptidases (leucine aminopeptidase and carboxypeptidases), and the tissue proteases (cathepsins). After a brief summary of the physical and biochemical properties of each enzyme, a critical appraisal is made of its potential and limitations as the enzyme is used in clinical medicine. This review concentrates on a delineation of the more important of the recent contributions, a discussion of certain controversial areas, with speCial emphasis on the therapeutic applications and the suggestion of certain fields of investigation which may require more attention in the future.