Understanding mechanisms involved in the production of Abeta has long been the central focus of cell biologists engaged in molecular AD research. The discovery of two genes that encode homologous polytopic membrane proteins termed Presenilins (PS), has lead to several exciting recent findings on the proteolytic processes responsible for generating the COOH-terminus of Abeta. What we now know is that PS proteins play an important role in Abeta production and are considered one of the therapeutic targets. Here I have reviewed the vast literature on the biology of PS, especially focusing on PS endoproteolysis and the accumulation of stable PS derivatives that are likely the functional units.