Clostridial neurotoxins from the botulinum neurotoxin (BoNT) family are protein complexes, derived from the bacterium Clostridium botulinum, which potently inhibit acetylcholine release and result in a reversible blockade of the neuromuscular junction. This feature led to the clinical development of BoNT-A for a number of neuromuscular disorders. BoNT-A toxins are commercially available as three different preparations: Dysport/Azzalure, Botox/Vistabel, and Xeomin/Bocouture. Although BoNT-A preparations have not yet been approved for the treatment of pain, a substantial body of preclinical and clinical evidence shows that BoNT-A is effective in treating a number of different types of pain. It is thought to exert an analgesic effect both via muscle-relaxant properties and also directly, via inhibition of nociceptive neuropeptides. This review explores the mechanistic basis of this analgesic effect, summarizing current knowledge of the structure-function relationship of BoNT and discussing effects on both motor and pain neurons. For a complete picture of the analgesic properties of BoNT-A, clinical evidence of efficacy in myofascial pain and neuropathic pain is considered in tandem with a mechanistic rationale for activity. Patients experiencing chronic pain are clear candidates for treatment with a modified clostridial endopeptidase that would provide enduring inhibition of neurotransmitter release. A strong preclinical evidence base underpins the concept that re-engineering of BoNT could be used to enhance the analgesic potential of this neurotoxin, and it is hoped that the first clinical studies examining re-engineered BoNT-A will confirm this potential.