The accumulation of the amyloid-beta peptide (Abeta) continues to emerge as a central factor in Alzheimer's disease (AD). In recent years attention has been drawn to clearance mechanisms of Abeta as evidence suggests reduced clearance may be linked to late-onset AD. Direct degradation of Abeta by endopeptidases has emerged as one critical pathway of clearance. Of particular interest are endopeptidases that are sensitive to the neprilysin inhibitors thiorphan and phosphoramidon (i.e. "NEP-like") as these inhibitors induce a dramatic increase in Abeta levels resulting in rapid plaque formation in wild-type rodents. This review focuses on neprilysin (NEP) and on another NEP-like endopeptidase termed neprilysin-2 (NEP2). The involvement of these endopeptidases in AD and the state of their therapeutic development are discussed.