Foot-and-mouth disease virus (FMDV) has been one of the pioneering viral systems in the development of synthetic peptides as vaccines. Protection against FMDV infection is associated with the induction of neutralising antibodies. Therefore, attempts have been made to identify peptides capable of eliciting protective humoral responses. Peptides based on a continuous, immunodominant B cell site on the capsid protein VP1 have been shown to confer limited protection in natural hosts. This probably reflects the difficulties in reproducing the immunogenicity of an entire viral particle by using a much simpler synthetic antigen, due to: (i) the polymorphism of the class II MHC; (ii) the adequate presentation to the immune system of the peptides, and (iii) the difficulties of achieving protection against a highly variable RNA virus, which may favour selection of virus antigenic variants. The improvement of FMD peptide vaccines, and the development of in vitro alternatives to in vivo immunogenic assays require further understanding of the immune mechanisms leading to protection against this important animal virus disease.