Our understanding of the genetic basis of host specialization in insects is limited to basic information on the number and location of genetic factors underlying changes in conspicuous phenotypes. We know nothing about general patterns of molecular evolution that may accompany host specialization but are not traceable to a single prominent phenotypic change. Here, I describe changes in the entire repertoire of 136 olfactory receptor (Or) and gustatory receptor (Gr) genes of the recently specialized vinegar fly Drosophila sechellia. I find that D. sechellia is losing Or and Gr genes nearly 10 times faster than its generalist sibling Drosophila simulans. Moreover, those D. sechellia receptors that remain intact have fixed amino acid replacement mutations at a higher rate relative to silent mutations than have their D. simulans orthologs. Comparison of these patterns with those observed in a random sample of genes indicates that the changes at Or and Gr loci are likely to reflect positive selection and/or relaxed constraint associated with the altered ecological niche of this fly.comparative genomics ͉ gustatory receptor ͉ host adaptation ͉ lineage-specific ͉ olfactory receptor H ost specialization and host shifts in insects that feed on plants provide excellent opportunities to study the genetic basis of ecological adaptation. Until now, however, this endeavor has been limited to attempts to map factors responsible for conspicuous phenotypic changes that accompany the ecological shifts (e.g., refs. 1-5). We know nothing about genetic changes whose individual effects are subtle, but whose combined presence may leave a striking signature on the genomes of specializing or host-shifting insects.For example, insects evaluate their environment largely by smell and taste, and we might therefore expect their chemical sensory systems to evolve during host specialization or shifts. The acquisition of a novel host may drive the adaptive divergence of sensory systems by positive selection, and the abandonment of an ancestral host may result in the deterioration of older sensory adaptations by genetic drift (or positive selection). Despite their potentially subtle phenotypic effects, such changes are likely to be pervasive (particularly because new host plants challenge insects with the task of recognizing and responding not only to a new food but often also to novel toxins, bacteria, fungi, predators, parasitoids, pupation sites, and mating environments) and are best detected by examining entire genomes or large groups of genes simultaneously.The olfactory receptor (Or) and gustatory receptor (Gr) gene families encode a diverse group of transmembrane proteins that bind volatile and soluble chemicals from the environment and trigger nerve impulses to the brain (6). Individual receptor genes in insects are highly divergent (paralogous genes from a single species often sharing Ͻ20% of their amino acids), are expressed in narrow subsets of olfactory and gustatory neurons from well defined regions of smell and taste organs, and la...