It started as a matter of guilt by association. Presenilin mutations have been blamed for most autosomal dominant forms of familial Alzheimer disease. And many had proposed that presenilin might play a role in the γ-secretase activity that cleaves amyloid precursor protein to create the plaque-forming amyloid β. When researchers finally pared down the exact actors involved in this proteolytic reaction, however, they found more than they bargained for. Since then, studies have refocused on the vagaries of this unique and seemingly important protease family.