Phlebotomus papatasi sand flies, the vectors of Leishmania major, differ genetically in their susceptibility to the pathogens. The costs of infection appear to be so great that selection against Leishmania-susceptible flies could presumably occur, unless susceptibility is compensated for by some advantage. Foci of P. papatasi-transmitted L. major are mainly found in arid habitats where seasonal stress of dehydration and heat reduces the quantity of sugar in plant leaves. The sand flies feed on these leaves and with the lack of essential sugar only a few survive long enough to deposit eggs and transmit Leishmania. This association suggested that susceptibility to L. major infection may be linked with advantageous tolerance of sugar deprivation. Here we show that desert sand flies, provided with excess sugar, became progressively resistant to infection. Selection for survival under sugar-poor conditions increased the susceptibility of parent and first-generation offspring by more than 2-fold. The leaves of plants, on which flies naturally feed, contain more sugar in irrigated than in arid habitats. About 85% of first-generation flies colonized from a desert habitat retain experimental Leishmania infection compared to 25% of offspring of flies from irrigated sites.