Abstract Foot and mouth disease (FMD) is a highly infectious and economically devastating disease of livestock. Although vaccines, available since the early 1900s, have been instrumental in eradicating FMD from parts of the world, the disease still affects millions of animals around the globe and remains the main sanitary barrier to the commerce of animals and animal products. Currently available inactivated antigen vaccines applied intramuscularly to individual animals, confer serotype and subtype specific protection in 1–2 weeks but fail to induce long-term protective immunity. Among the limitations of this vaccine are potential virus escape from the production facility, short shelf life of formulated product, short duration of immunity and requirement of dozens of antigens to address viral antigenic diversity. Here we review novel vaccine approaches that address some of these limitations. Basic research and the combination of reliable animal inoculation models, reverse genetics and computational biology tools will allow the rational design of safe and effective FMD vaccines. These vaccines should address not only the needs of FMD-free countries but also allow the progressive global control and eradication of this devastating disease.