Attenuated Salmonella enterica serovar Typhi (S. Typhi) strains can serve as safe and effective oral vaccines to prevent typhoid fever and as live vectors to deliver foreign antigens to the immune system, either by the bacteria expressing antigens through prokaryotic expression plasmids or by delivering foreign genes carried on eukaryotic expression systems (DNA vaccines). The practical utility of such live vector vaccines relies on achieving a proper balance between minimizing the vaccine's reactogenicity and maximizing its immunogenicity. To advance to clinical trials, vaccine candidates need to be pre-clinically evaluated in relevant animal models that attempt to predict what their safety and immunogenicity profile will be when administered to humans. Since S. Typhi is a human-restricted pathogen, a major obstacle that has impeded the progress of vaccine development has been the shortcomings of the animal models available to assess vaccine candidates. In this review, we summarize the usefulness of animal models in the assessment of the degree of attenuation and immunogenicity of novel attenuated S. Typhi strains as vaccine candidates for the prevention of typhoid fever and as live vectors in humans.