Studies of the pathogenesis of Salmonella at the molecular level have led to the identification of several classes of genes that are involved in survival in the host. This has led to the availability of a panel of attenuating lesions which are now being used to develop several rationally attenuated strains which are being evaluated as oral vaccines against human and animal salmonellosis. Much effort has been directed towards the development of a more efficacious single dose oral typhoid vaccine and there are now several candidates in Phase 1 studies. The successful development of a genetically defined oral typhoid vaccine will not only be a major step forward in the control of typhoid but will pave the way for development of practical human vaccines based on using the strain to deliver heterologous antigens to the human immune system. We have concentrated on developing a single dose oral tetanus vaccine based on constructing strains expressing fragment C (a non-toxic immunogenic protein derived from tetanus toxin). Several different promotors have been used for controlling the expression of fragment C and these have been introduced into double aro mutants of S. typhimurium and compared for their ability to elicit protective immune responses in mice. This work has demonstrated that it is possible to protect mice against tetanus toxin challenge after a single oral dose of one of these recombinant Salmonella strains. Analogous hybrid S. typhi double aro mutants have now been constructed for potential use in humans.