Studies demonstrating that accumulation and aggregation of the amyloid β protein (Aβ) within the brain is likely to cause Alzheimer's disease (AD) have provided the rationale for therapeutic strategies aimed at influencing Aβ production, aggregation and clearance. γ-secretase catalyzes the final cleavage that releases the Aβ from its precursor; therefore, it is a potential therapeutic target for the treatment of AD. Recent data show that the polytopic membrane proteins presenilin 1 and presenilin 2 are either catalytic components or essential co-factors of a membrane-bound proteolytic complex that possesses γ-secretase activity. Although recent findings demonstrating that γ-secretase inhibitors bind directly to presenilins (PSs) further support a catalytic role for PSs in γ-secretase cleavage, additional studies are still needed to clarify the role of PSs in γ-secretase cleavage and theuse of targeting PSs to reduce Aβ production.