The neprilysin (NEP) family of zinc metallopeptidases includes neprilysin, endothelin-converting enzyme-2 (ECE-2), PEX, damage induced neuronal endopeptidase (DINE), Kell and several neprilysin-like proteins. Neprilysin is expressed at the cell surface of a variety of cell types. Enzymatically, neprilysin functions both as an endopeptidase with a thermolysin-like specificity and as a dipeptidylcarboxypeptidase. Neprilysin has been shown to be involved in the degradation of enkephalins in the mammalian brain and the inactivation of circulating atrial natriuretic peptide. Neprilysin has also been identified as the common acute lymphoblastic leukemia antigen (CALLA), and to be expressed on the surface of lymphocytes in some disease states. These and other observations have resulted in considerable clinical interest in neprilysin as a potential target for analgesics and antihypertensive drugs. Neprilysin is also a major degrading enzyme of amyloid-beta peptide (A-beta) in the brain, indicating that down-regulation of neprilysin activity, which could be caused by aging, can contribute to the development of Alzheimers disease by promoting A-beta accumulation.