A number of cell surface growth factor receptors are subject to presenilin-dependent regulated intramembrane proteolysis (PS-RIP) after ligand binding and/or ectodomain cleavage. PS-RIP is mediated by a highly conserved multi-component membrane-bound protease, termed gamma-secretase, responsible for generating Alzheimer's disease (AD)-associated Abeta peptide from its membrane-bound beta-amyloid precursor protein (APP), as well as for cleaving a number of other type-I membrane receptors. PS-RIP is a conserved cellular process by which cells transmit signals from one compartment to another, including the liberation of membrane-bound transcription factors. Recent studies indicate that PS-RIP also mediates the proteolytic inactivation of heteromeric receptor complexes by removing the transmembrane domains required for receptor-receptor interaction. Thus, PS-RIP appears to regulate diverse cellular pathways either by generating soluble effectors from membrane-bound precursors, or by removing the transmembrane domain of a membrane-tethered signaling component.