In Drosophila, adaptation to xeric environments presents many challenges, greatest among them the maintenance of water balance. Drosophila mojavensis, a cactophilic species from the deserts of North America, is one of the most desiccation resistant in the genus, surviving low humidity primarily by reducing its metabolic rate. Genetic control of reduced metabolic rate, however, has yet to be elucidated. We utilized the recently sequenced genome of D. mojavensis to create an oligonucleotide microarray to pursue the identities of the genes involved in metabolic regulation during desiccation. We observed large differences in gene expression between male and female D. mojavensis as well as both quantitative and qualitative sex differences in their ability to survive xeric conditions. As expected, genes associated with metabolic regulation and carbohydrate metabolism were differentially regulated between stress treatments. Most importantly, we identified four points in central metabolism (Glyceraldehyde 3-phosphate dehydrogenase, transaldolase, alcohol dehydrogenase, and phosphoenolpyruvate carboxykinase) that indicate the potential mechanisms controlling metabolic rate reduction associated with desiccation resistance. Furthermore, a large number of genes associated with vision pathways also were differentially expressed between stress treatments, especially in females, that may underlie the initial detection of stressful environments and trigger subsequent metabolic changes.