Botulinum neurotoxin A (BoNT/A) is a metalloprotease that enters peripheral motor nerve terminals and blocks the release of acetylcholine via the specific cleavage of the synaptosomal-associated protein of 25-kDa. Localized injections of BoNT/A are widely employed in clinical neurology to treat several human diseases characterized by muscle hyperactivity. It is generally assumed that the effects of BoNT/A remain localized to the injection site. However, several neurophysiological studies have provided evidence for central effects of BoNT/A, raising the issue of how these actions arise. Here we review these data and discuss the possibility that retrograde axonal transport of catalytically active BoNT/A may explain at least some of its effects at the level of central circuits.