Deposition of the amyloid-beta protein (Abeta) in the form of cerebral plaques is a defining pathological feature of Alzheimer's disease (AD), and all AD-causing genes identified to date affect Abeta production or deposition. For these reasons, the two proteases, beta- and gamma-secretases, that cut out Abeta from the amyloid-beta precursor protein (APP) are considered important targets for the development of therapeutics for AD. AD-causing mutations in the presenilin genes alter y-secretase activity, increasing production of the more deleterious 42-residue form of Abeta. Pharmacological profiling, site-directed mutagenesis, knockout studies, affinity labeling, and activity-dependent chromatography all strongly support the hypothesis that presenilin is an integral component of gamma-secretase, a founding member of an emerging class of polytopic membrane proteases. Gamma-Secretase/ presenilin also cleaves other proteins that are important for critical signaling events (the Notch family of receptors), raising concerns about mechanism-based toxicities that might arise as a consequence of inhibiting this protease. In light of these findings, the potential of gamma-secretase vis-à-vis beta-secretase as therapeutic targets for the prevention or treatment of AD will be discussed.