We combined transcriptional profiling and quantitative genetic analysis to elucidate the genetic architecture of olfactory behavior in Drosophila melanogaster. We applied whole-genome expression analysis to five coisogenic smell-impaired (smi) mutant lines and their control. We used analysis of variance to partition variation in transcript abundance between males and females and between smi genotypes and to determine the genotype-by-sex interaction. A total of 666 genes showed sexual dimorphism in transcript abundance, and 530 genes were coregulated in response to one or more smi mutations, showing considerable epistasis at the level of the transcriptome in response to single mutations. Quantitative complementation tests of mutations at these coregulated genes with the smi mutations showed that in most cases (67%) epistatic interactions for olfactory behavior mirrored epistasis at the level of transcription, thus identifying new candidate genes regulating olfactory behavior.