The immune system is unable to determine whether material it encounters is deleterious, benign, or even beneficial to the organism. This presents a significant challenge when protein-based biological therapies, such as botulinum toxin, are administered to patients. Many factors combine to influence the likelihood and the magnitude of an immune response if a response is elicited. Those factors intrinsic to antigens that heighten their immunogenicity include nonhuman origin, larger molecules, and aggregated forms of the protein. Extrinsic factors also must be considered, such as the presence of adjuvants in the formulation, either intended or unintended; increasing amounts of antigen within specific dosing ranges; frequent dosing; and, finally, the genetic predisposition of the patient. Once present, not all immune responses preclude the biological therapy from being clinically effective. Only antibodies that bind botulinum toxin in a manner that neutralizes its biological activity will attenuate its effect on the neuromuscular junction. The majority of anti-toxin antibodies do not affect its function. Finally, although crossreactivity has been reported among the seven botulinum toxin serotypes, non-neutralizing antibodies are present that recognize regions of similarity among the serotypes. No cross-neutralizing antibodies have been described in patients administered any of the toxin serotypes.