It is widely believed that the pathogenesis of Alzheimer's disease (AD) is intimately, if not causatively, associated with the deposition of approximately 4 kDa beta-amyloid (A beta) peptides in the cerebral cortex and hippocampus of affected individuals. A beta peptides are liberated from transmembrane proteins, termed beta-amyloid precursor proteins (APP), by the concerted action of beta- and gamma-secretase(s). Whereas the identity of beta-secretase is no longer in question, the identity of gamma-secretase, which is responsible for the intramembranous processing of APP, has never been more enigmatic. Considerable evidence has accrued to impugn the presenilins (PS) as the executioners of intramembranous processing of APP. Here, we summarize these observations and review recent evidence that argues against the prevailing hypothesis that PS function as gamma-secretases.