gamma-Secretase catalyzes the cleavage at the carboxyl terminus of A beta to release it from the APP. While gamma-secretase is a major therapeutic drug target for the treatment of Alzheimer's disease (AD), it appears to be an unusual proteolytic activity, and, to date, no protease responsible for this activity has been identified. Based on studies of APP transmembrane domain (TMD) mutants, it is apparent that there are multiple pharmacologically distinct gamma-secretase activities that are spatially restricted and that presenilins (PS) regulate cleavage by gamma-secretases in a protease independent fashion. Based on these studies, we propose a multiprotease model for gamma-secretase activity and predict that the gamma-secretases are likely to be closely related proteases.