Typhoid fever is a classical human systemic infection caused by Salmonella enterica serovar Typhi (S. typhi). It was identified one hundread years agoand continues asa persistent global health problem. In addition to the disease burden and mortality, the emergence of multidrug-resistant strains of S. typhi now pose a new level of challenges. Because S. typhi is a human restricted pathogen, typhoid fever research has been limited due to the lack of appropriate animal models. Recently, humanized immune system (HIS) mice and inducible nitric oxide synthase (iNOS) knockout mice emerge as two useful tools in the study of pathogenesis of S. typhi and immune responses. The merit and shortage of HIS and iNOS mice are reviewed in this article.