'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.