show Abstracthide AbstractLeishmania are parasites that cause leishmaniasis, a compendium of serious diseases that affect millions of people, mainly across the subtropics and tropics. They are transmitted to humans by phlebotomine sand flies. However, despite establishment in the insect's midgut being key to transmission, early infection events inside the insect are still unclear. Here, we study the gene expression response of the insect vector to a Leishmania parasite that is able to establish infection (L. major) one that is unable to do so (L. donovani) as well as one that is not a natural parasite of sand flies (Herpetomonas muscarum). We found that responses following any of the infected blood meals was very similar to uninfected blood meal. However, changes post-blood meal from day 1 to day 9 were dramatic. As a blood feeding insect can accumulate five times its weight in one blood meal, this seems to be the most important physiological change rather than the presence of the parasite. The latter might be just one in a number of microbes the insect encounters. This will generate new thinking around the concept of stopping transmission by controlling the parasite inside the insect.