Over the years the presenilins (PSENs), a family of multi-transmembrane domain proteins, have been ascribed a number of diverse potential functions. Recent in vivo evidence has supported the existence of PSEN functions beyond its well-established role in regulated intramembrane proteolysis. In this review, we will briefly discuss the ability of PSEN to modulate cellular signaling pathways through γ-secretase cleavage of transmembrane proteins. Additionally, we will critically examine the proposed roles of PSEN in the regulation of β-catenin function, protein trafficking, calcium regulation, and apoptosis.