Presenilins are the catalytic subunits of larger tetrameric γ-secretase complexes. The degradome of these aspartyl proteases consists of at least 60 different substrates. γ-Secretase is key to regulated intramembrane proteolysis, releasing protein fragments that potentially transduce signals at both sides of the cell membrane. Characteristic for this novel form of cellular signaling is its irreversible nature, providing direction to biological processes. We discuss recent insights in structure-function and assembly of the γ-secretase complexes and emerging insights in the regulation of the activity of these enzymes. This novel knowledge will help to develop better drugs for Alzheimer's disease and cancer. We critically evaluate literature that proposes presenilin functions outside of the γ-secretase complex.