J. Neurochem.(2012)120(Suppl. 1), 34–45.Absract‘Secretase’ is a generic term coined more than 20 years ago to refer to a group of proteases responsible for the cleavage of a vast number of membrane proteins. These endoproteolytic events result in the extracellular or intracellular release of soluble metabolites associated with a broad range of intrinsic physiological functions. α‐Secretase refers to the activity targeting the amyloid precursor protein (APP) and generating sAPPα, a soluble extracellular fragment potentially associated with neurotrophic and neuroprotective functions. Several proteases from the a disintegrin and metalloproteinase (ADAM) family, including ADAM10 and ADAM17, have been directly or indirectly associated with the constitutive and regulated α‐secretase activities. Recent evidence in primary neuronal cultures indicates that ADAM10 may represent the genuine constitutive α‐secretase. Mainly because α‐secretase cleaves APP within the sequence of Aβ, the core component of the cerebral amyloid plaques in Alzheimer’s disease, α‐secretase activation is considered to be of therapeutic value. In this article, we will provide a historical perspective on the characterization of α‐secretase and review the recent literature on the identification and biology of the current α‐secretase candidates.