Infection with vector-borne pathogens starts with the inoculation of these pathogens during blood feeding. In endemic regions, the population is regularly bitten by naive vectors, implicating a permanent stimulation of the immune system by the vector saliva itself (pre-immune context). Comparatively, the number of bites received by exposed individuals from non-infected vectors is much higher than the bites from infected ones. Therefore, vector saliva and the immunological response in the skin may play an important role, so far underestimated, in the establishment of anti-pathogen immunity in endemic areas. Hence, the parasite biology and the disease pathogenesis in "saliva-primed" and "saliva-unprimed" individuals must be different. This integrated view on how the pathogen evolves within the host together with vector salivary components, which are known to be endowed with a variety of pharmacological and immunological properties, must remain the focus of any investigational study dealing with vector-borne diseases. Considering this three-way partnership, the host skin (immune system), the pathogen, and the vector saliva, the approach that consists in the validation of vector saliva as a source of molecular entities with anti-disease vaccine potential has been recently a subject of active and fruitful investigation. As an example, the vaccination with maxadilan, a potent vasodilator peptide extracted from the saliva of the sand fly Lutzomyia longipalpis, was able to protect against infection with various leishmanial parasites. More interestingly, a universal mosquito saliva vaccine that may potentially protect against a range of mosquito-borne infections including malaria, dengue, Zika, chikungunya and yellow fever. In this review, we highlight the key role played by the immunobiology of vector saliva in shaping the outcome of vector-borne diseases and discuss the value of studying diseases in the light of intimate cross talk among the pathogen, the vector saliva, and the host immune mechanisms.(AU)