Presenilins (PS) constitute a fascinating family of proteins that play crucial roles in several major signalling processes involved in key cellular functions and are also closely associated with dysfunction in Alzheimer's disease (AD). Presenilin-dependent intramembrane cleavage of transmembrane proteins such as amyloid beta precursor protein (AbetaPP) and Notch resides in a high-molecular-weight gamma-secretase protein complex, of which at least five core components have now been identified. Remarkably, it has now become evident that presenilin-dependent gamma-secretase activity extends beyond its role in AbetaPP and Notch cleavages to have a generic role in the regulated intramembranous cleavage of certain membrane proteins. Actually, a new picture is emerging in which cells can relay signals from the extracellular space to their interior through presenilin-dependent proteolysis within the membrane-spanning regions of type 1 integral membrane proteins to generate potential transcriptionally active intracellular fragments. This review deals with the complex biology of presenilins and focuses more specifically on recent developments regarding the composition, assembly and regulation of the gamma-secretase protein complex, its substrates and its implications for cellular signalling.