The wide variety of clinical presentations of these diseases is a reflection of the numerous host-, parasite- and vector-derived factors playing a role in their pathogenesis. Among these factors, the infection-potentiating effect of sand fly salivary molecules has generated a great deal of excitement in the research community because: 1) it provides clues about immunobiological determinants of resistance or susceptibility to Leishmania infection and 2) it provides additional targets for vaccines to prevent leishmaniasis. Sand fly saliva plays an important role in the transmission of Leishmania parasites, facilitating their survival and dissemination in tissues of the vertebrate hosts by promoting a Th2-skewed immune response at the bite site. Vaccines directed to sand fly saliva are expected to induce protective immunity by neutralizing the biological activity of salivary immuno-modulators and by generating a tissue microenvironment that promotes the destruction of parasites delivered, along with saliva, while sand flies take a blood meal. Epidemiological evidence linking resistance to Leishmania infection in adults living in endemic areas with production of antibodies to sand fly salivary antigens, indicates that protective anti-salivary immunity can be acquired through chronic exposure to the bite of sand flies. Given that arthropod saliva is a cocktail of molecules selected through evolution to optimize access to the blood of vertebrates and minimize immune reactions, it is not surprising that anti-salivary immunity takes so long to develop under natural conditions. The fate of arthropod-salivary proteins delivered at the bite site is an additional factor that might determine the speed at which the vertebrate host acquires protective anti-salivary immunity. This is because neutrophils, one of the major components of the wound resolution machinery of vertebrates, can degrade arthropod salivary proteins before they are taken up by professional antigen-presenting cells. Histopathological analysis of sand fly bite sites indicates that neutrophils are indeed a dominant component of the early inflammatory response to sand fly bites in naive animals. Theoretically, the acquisition of natural immunity to sand fly saliva would be kinase inhibitors accelerated if changes introduced into vertebrate tissues decrease the influx of neutrophils to the bite site or, alternatively, improve access of professional antigen-presenting cells to salivary proteins before they are degraded by neutrophilderived enzymes. The former can be induced with drugs or antineutrophil antibodies, but the associated systemic vulnerability to bacterial infections is a major drawback of this approach.