Botulinum neurotoxin is the neuromuscular poison that is responsible for the fatal disease botulism. This toxin is also a valued therapeutic agent in the treatment of an increasing number of neuromuscular disorders. Unfortunately, in the wrong hands, botulinum neurotoxin is also a deadly biological "weapon. The diverse health consequences of botulinum neurotoxin combined with the increased threat of bioterrorism underscore the profound importance of understanding exactly how this toxin exerts its effects on the clinically relevant mammalian target site, the neuromuscular junction. Despite the fact that a great deal has been learned about the cellular actions of botulinum neurotoxin during the past three decades, questions still remain. For example, what protein or proteins mediate transport of the toxin into the cholinergic nerve terminal? What factors control the duration of toxin action in the nerve terminal? Until recently, scholarly pursuit of such questions was technically challenging in neuromuscular tissues. Recent advancements in biotechnology have now made it feasible to pursue these important issues at the neuromuscular junction and to correlate biochemical studies in nontarget tissues with clinically relevant functional outcomes. This narrative reviews our current understanding of the actions of botulinum neurotoxin at the neuromuscular junction, presents recent findings from our own work in neuromuscular tissues, and encourages future studies regarding botulinum neurotoxin at its target site.