Alzheimer's disease is the most common form of dementia and a major public health problem. The amyloid hypothesis suggests that Alzheimer's disease is due to the abnormal accumulation of amyloid-beta protein (A beta) in affected brain regions. Rational therapies aimed at reducing amyloid burden in brain are currently being pursued in preclinical and early clinical development. This review summarizes recent progress in understanding the beta- and gamma-secretase activities required for the formation of A beta peptide and discusses therapeutic strategies aimed at inhibiting these activities. Recent progress in the identification of small molecule inhibitors of these secretases is also reviewed.