Phenserine, a derivative of physostigmine, was first described as an inhibitor of acetylcholinesterase (AChE) and was shown to improve cognition in various experimental paradigms in rodents and dogs. It was clinically tested for Alzheimer's disease, with moderate success in initial Phase II studies. Phenserine deserves attention for an additional quality of action: in addition to inhibiting AChE, it modulates the amount of β-amyloid precursor protein (APP) in neuronal cell culture by reducing APP translation. This effect probably involves interaction of phenserine with a regulatory element in the 5'-untranslated region of the APP gene that controls APP expression. Phenserine apparently reduces translational efficiency of APP mRNA into protein, a process that may involve an interaction with iron and/or an iron-responsive element. As a consequence, phenserine reduces β-amyloid peptide (Aβ) formation in vitro and in vivo. Phenserine is also unique because of differing actions of its enantiomers: (−)-phenserine is the active enantiomer for inhibition of AChE, whereas (+)-phenserine (‘posiphen’) has weak activity as an AChE inhibitor and can be dosed much higher. Both enantiomers are equipotent in downregulating APP expression. (+)-Posiphen may be a promising drug, either alone or in combination with (−)-phenserine, to attenuate the progression of Alzheimer's disease.