γ-Secretase — a protease that cleaves within the membrane — was first recognized for its role in the production of amyloidogenic Aβ peptides, but was subsequently found to mediate Notch signalling by releasing the Notch-receptor intracellular domain. Many other γ-secretase substrates have recently been identified, which indicates a broader biological function for this unusual protease. Emerging evidence implies that whereas some intracellular cleavage products of γ-secretase function as signalling molecules, others might simply be intermediates that are destined for degradation.