Inhibiting the production of amyloid-beta by antagonising gamma-secretase activity is currently being pursued as a therapeutic strategy for Alzheimer's disease (AD). However, early pre-clinical studies have demonstrated that disruption of presenilin-dependent gamma-secretase alters many presenilin-dependent processes, leading to early lethality in several AD model organisms. Subsequently, transgenic animal studies have highlighted several gross developmental side effects arising from presenilin deficiency. Partial knockdown or tissue-specific knockout of presenilins has identified the skin, vascular and immune systems as very sensitive to loss of presenilin functions. A more appreciative understanding of presenilin biology is therefore demanded if gamma-secretase is to be pursued as a therapeutic target. Herein we review the current understanding of gamma-secretase complexes; their regulation, abundance of interacting partners and diversity of substrates. We also discuss regulation of the gamma-secretase complexes, with an emphasis on the functional role of presenilins in cell biology.