Dissecting the interaction between bacterial and host proteins is fundamental in understanding pathogenesis. It is also very helpful for exploring new therapeutic approaches, either preventive or curative. Here, we describe different techniques, which allowed us to detect new molecules involved in the binding and infection of the bacterium Francisella tularensis, on human cells. This facultative intracellular pathogen is the causative agent of tularemia and is considered as a bio-threatening agent. The privileged host cells are monocytes and macrophages. We used both "in vitro" and "in vivo" experiments to explore the modulation of F. tularensis infection and thereafter determine a bacterial ligand and its host receptor molecule.