Suitable alterations in gene expression are believed to allow animals to survive drastic changes in environmental conditions. Drosophila melanogaster larvae cease eating and exit moist food to search for dry pupation sites after the foraging stage in what is known as the wandering stage. Although the behavioral change from foraging to wandering causes desiccation stress, the mechanism by which Drosophila larvae protect themselves from desiccation remains obscure. Here, we identified a gene, CG14686 (designated as Desiccate (Desi)), whose expression was elevated during the wandering stage. The Desi expression level was reversibly decreased by transferring wandering larvae to wet conditions and increased again by transferring them to dry conditions. Elevation of Desi expression was also observed in foraging larvae when they were placed in dry conditions. Desi encoded a 261-amino acid single-pass transmembrane protein with notable motifs, such as SH2 and PDZ domain-binding motifs and a cAMP-dependent protein kinase phosphorylation motif, in the cytoplasmic region, and its expression was observed mainly in the epidermal cells of the larval integuments. Overexpression of Desi slightly increased the larval resistance to desiccation stress during the second instar. Furthermore, Desi RNAi larvae lost more weight under dry conditions, and subsequently, their mortalities significantly increased compared with control larvae. Under dry conditions, consumption of carbohydrate was much higher in Desi RNAi larvae than control larvae. Based on these results, it is reasonable to conclude that Desi contributes to the resistance of Drosophila larvae to desiccation stress.A wide variety of stressful stimuli change patterns of gene expression, which enables animals to adapt to stress, and such changes in gene expression are believed to allow them to survive drastic environmental changes. Activation of heat shock protein genes (hsp) is a typical example; all organisms express a particular set of hsp genes in response to stressors such as temperature extremes, aversive chemical application, anoxia, and many other environmental injuries (1, 2). Hsp proteins are generally divided into three families: the 90-kDa, 70-kDa, and small heat shock proteins (3). It has been reported that a nonlethal desiccation at 0% relative humidity (RH) 2 enhanced transcriptional levels of the two hsp genes, hsp70 and hsp23, in pupae of the flesh fly Sarcophaga crassipalpis (4). Although the two hsp transcripts were up-regulated in response to desiccation, the up-regulation was less dramatic than that elicited by heat shock, and desiccation failed to generate tolerance to high or low temperatures. Recently, it has been also reported that dehydration elicited expression of hsp70 in three mosquito species, Aedes aegypti, Anopheles gambiae, and Culex pipiens, but hsp90 expression levels remained fairly constant. Furthermore, injection of dsRNA to knock down expression of hsp70 and hsp90 significantly decreased survival rates of A. aegypti under dehydration (5)....