In the non-amyloidogenic pathway, the Alzheimer's amyloid precursor protein (APP) is cleaved within the amyloid-β domain by α-secretase precluding deposition of intact amyloid-β peptide. The large ectodomain released from the cell surface by the action of α-secretase has several neuroprotective properties. Studies with protease inhibitors have shown that α-secretase is a zinc metalloproteinase, and several members of the adamalysin family of proteins, tumour necrosis factor-α convertase (TACE, ADAM17), ADAM10, and ADAM9, all fulfil some of the criteria required of α-secretase. We review the evidence for each of these ADAMs acting as the α-secretase. What seems to be emerging from numerous studies, including those with mice in which each of the ADAMs has been knocked out, is that there is a team of zinc metalloproteinases able to cleave APP at the α-secretase site. We also discuss how upregulation of α-secretase activity by muscarinic agonists, cholesterol-lowering drugs, steroid hormones, non-steroidal anti-inflammatory drugs, and metal ions may explain some of the therapeutic actions of these agents in Alzheimer's disease. © 2003 Wiley-Liss, Inc.