Botulinum toxin type A is a 150 kD protein produced by Clostridium botulinum, which exists in a complex with up to six additional proteins. The ability of botulinum toxin to inhibit acetylcholine release at the neuromuscular junction has been exploited for use in medical conditions characterized by muscle hyperactivity. As such, botulinum toxin is widely recommended by international treatment guidelines for movement disorders and it has a plethora of other clinical and cosmetic indications. The chronic nature of these conditions requires repeated injections of botulinum toxin, usually every few months. Multiple injections can lead to secondary treatment failure in some patients that may be associated with the production of neutralizing antibodies directed specifically against the neurotoxin. However, the presence of such antibodies does not always render patients non-responsive. The reported prevalence of immunoresistance varies greatly, depending on factors such as study design and treated indication. This review presents what is currently known about the immunogenicity of botulinum toxin and how this impacts upon patient non-response to treatment. The complexing proteins may act as adjuvants and stimulate the immune response. Their role and that of neutralizing and non-neutralizing antibodies in the response to botulinum toxin is discussed, together with an assessment of current neutralizing antibody measurement techniques. Botulinum toxin preparations with different compositions and excipients have been developed. The major commercially available preparations of botulinum toxin are Botox® (onabotulinumtoxinA; Allergan, Inc., Ireland), Dysport® (abobotulinumtoxinA; Ipsen Ltd, UK), and Xeomin® (incobotulinumtoxinA; botulinum toxin type A [150 kD], free from complexing proteins; NT 201; Merz Pharmaceuticals GmbH, Germany). The new preparations of botulinum toxin aim to minimize the risk of immunoresistance in patients being treated for chronic clinical conditions.