Vaccination is an efficient and cost-effective form of preventing infectious diseases. However, most currently available vaccines are delivered by injection, which makes mass immunization more costly and less safe, particularly in resource-poor developing countries. Oral vaccines have several attractive features compared with parenteral vaccines, but studies on their use have been limited almost exclusively to protection against mucosally transmitted pathogens. Their potential for controlling non-mucosally transmitted diseases has not yet been appreciated in general. In this article, we provide evidence that oral immunization is a feasible alternative for preventing infections transmitted through non-mucosal routes, including infections such as malaria, Japanese encephalitis and hepatitis B. Although there are still hurdles to overcome before such approaches can be deployed widely, recent progress in the oral vaccination field and the availability of a range of delivery systems offers hope for the development of a larger number of oral vaccines.