Generation of Amyloid peptide (Abeta) is at the beginning of a cascade that leads to Alzheimer's disease. Currenty, the mechanisms of Abeta generation and Abeta prevention are subject of intensive research. Amyloid precursor protein (APP), as well as beta- and gamma-secretases are the principal players involved in Abeta production, while alpha-secretase cleavage on APP prevents Abeta deposition. Inhibitors or modulators that target beta- and gamma-secretases as well as alpha-secretase activators are promising candidates for treatment of Alzheimer's disease. A deep knowledge of the secretases is required to develop disease modifying drugs that target them. The most challenging quest is to translate the growing knowledge about the cell biology of secretases and their mechanisms of action into effective therapeutics. Here, we review the main features of the secretases.