Salmonella enterica serovar Typhi (Typhi), the aetiologic agent of typhoid fever, is a human restricted pathogen. Elucidation of the interactions between the infected host and this pathogen is critical to understand infectious diseases but is deterred by a lack of in vivo infection assays, since Typhi uniquely infects humans and there is no suitable animal model. Macrophages can be used as an alternative model, as the ability to survive and replicate within these cells is thought to be one of the major pathogenesis determinants for Salmonella. Typhi genes that are expressed within human macrophages have been identified, as well as Typhi immunogenic proteins expressed in humans with typhoid. Known virulence factors of Salmonella are expressed during infection of macrophages, such as SPI-2 encoded genes, supporting the validity of the model; however, many genes of unknown functions are also expressed. The importance of these genes should be investigated during future studies aimed at elucidating the intracellular lifestyle of this human-specific pathogen. This review describes Typhi genes expressed during infection or involved in cell interaction.