The mammalian immune system is seen as an increasingly complex network of cells and factors that orchestrate generally targeted and appropriate immune responses to limit pathology caused by viruses, bacteria and fungi.  The initiation of the response that ultimately leads to the development of a protection against infection is key to our exploiting these responses to drive immunity through vaccination.  Natural immunity is highly regulated and these normal immunoregulatory processes are now known to be key to the lack of potent immune responses against some cancers.  The early immune activation events in experimental Salmonella infections highlight some of the key sensory pathways - the consequences of overt activation of innate and then adaptive immune responses on bacterial replication control and clearance, and the impact of early and inappropriate immunoregulation, will be discussed in the context of the experimental typhoid model.