Clostridial neurotoxins have profound effects on neuronal membrane traffic. Each of the toxins inhibits neurotransmission, cleaves a specific protein implicated in synaptic vesicle docking/fusion, and prevents the fusion of synaptic vesicles with the presynaptic membrane. Botulinum neurotoxin C is unique in that it proteolyzes two proteins (SNAP-25 and syntaxin) and is severely cytotoxic to developing and mature neurons in cell culture. Botulinum neurotoxin A uncouples vesicle endocytosis from exocytosis; it blocks synaptic vesicle exocytosis but allows stimulus-triggered synaptic vesicle membrane retrieval. Neuronal membrane gangliosides play an important role in tetanus toxin internalization and may be a functional component of the toxin receptor. Studies with chimeric toxins indicate that either the number or distribution of toxin receptors underlies the different effects of toxins on inhibitory and excitatory neurotransmitter release. Specific receptors likely account for the greater efficacy of botulinum neurotoxin A at nerve-muscle synapses and tetanus toxin at spinal cord synapses.