Mammalian proteases comprise both the peptidases or exopeptidases, which act at the N- or C-terminal positions of polypeptides, and the proteinases or endopeptidases, which are capable of cleaving peptide bonds in the central regions of polypeptides. Presumably the endopeptidases usually act first in the degradation of a protein molecule. The endopeptidases are classified in four distinct groups on the basis of the chemical nature of the groups responsible for catalytic activity. Because these chemical groupings are most reliably recognized by use of active-site directed inhibitors, inhibitors are often more important than substrates in the classification and identification of proteinases. The major characteristics of the serine, thiol, carboxyl, and metallo-proteinases are summarized. The activities of the proteinases in vivo are controlled by a powerful range of inhibitors, as well as other factors, and the properties of these also are summarized.