The endogenous opioid peptides enkephalins are degraded in vitro by several metallopeptidases (aminopeptidases, enkephalinase, dipeptidylaminopeptidases). Selective and mixed inhibitors of these enzymes were obtained by a rational approach taking into account crystallographic data on Thermolysin, a bacterial enzyme, used as model of metallopeptidase active site. This strategy is supported by recent cloning of enkephalinase. As expected, a physiological analgesia is produced by administration of inhibitors, especially kelatorphan and analogues, demonstrating unambiguously the implication of enkephalinase and aminopeptidase M in enkephalin metabolism. The intensive studies on endogenous opioid system have shown that inhibitors of enkephalin metabolism represent very useful probes and promising new analgesics.