Botulinum neurotoxin (BoNT), a product of Clostridium botulinum, reversibly inhibits the presynaptic release of the neurotransmitter acetylcholine at the neuromuscular junction. In addition, BoNT blocks the transmission of other substances involved in pain perception and, together with a soft-tissue anti-inflammatory effect, may play a role in analgesia. When first-line treatment fails, second-line therapies might include BoNT. Studies on chronic and recurrent pain using different mechanisms offer heterogenous results that must be validated and standardized. Plantar fasciitis, severe knee osteoarthritis, painful knee and hip arthroplasty, antalgic muscular contractures, and neuropathic and myofascial pain syndromes may benefit from the administration of BoNT. Research on this topic has revealed the main musculoskeletal conditions that can benefit from BoNT, stressing the effects, modalities of administration, doses, and schedule.