Leishmania spp. are polarized single-celled eukaryotic parasites, the perpetuation of which relies on two other organisms they "use" as hosts. One of the Leishmania host organisms is a blood-feeding female sand fly, the second host being a mammal that acts as a blood source for the female sand fly. Leishmania-hosting sand flies transmit the metacyclic promastigote developmental stage to the mammal skin. While many mammals are known to act as sand fly blood sources, only some of these mammals are/ will be "used" as Leishmania hosts. This host status means that skin as well as skin-distant tissues and cell lineages (mononuclear phagocytes and fibroblasts) of these mammals are rapidly and continuously remodelled as niches where Leishmania will deploy its developmental programs: it is noteworthy that without the deployment of the developmental program underlying Leishmania transmission from the mammal to the blood-searching and blood-feeding sand flies, the perpetuation of Leishmania will be suspended. While post genomic approaches are providing insight about some features of Leishmania major, Leishmania infantum/chagasi and Leishmania braziliensis, such approaches are not yet available for the natural hosts (wild rodents, wild sand flies) these Leishmania species "use" as hosts.