Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms. The presynaptic neurotoxins which interfere directly with the process of neurotransmitter release can be grouped in three large families: (1) the clostridial neurotoxins which act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; (2) the snake presynaptic neurotoxins with phospholipase A2 activity whose site of action is still undefined and which induce the release of acetylcholine followed by impairment of synaptic functions; (3) the excitatory latrotoxin-like neurotoxins which induce a massive release of neurotransmitter at peripheral and central synapses. In this paper, the first two families are considered in terms of their modes of action and in relation to their potential use in cell biology and neuroscience as well as the therapeutic utilisation of the botulinum neurotoxins in human diseases characterised by hyperfunction of cholinergic terminals.