By using a combination of global gene expression analysis and a mutant survey, we demonstrate that genes important for immunity, metabolism, olfaction, and protein acetylation regulate ethanol behavioral responses in Drosophila. Evidence for genes involved in each of these biological processes in regulating the effects of drugs of abuse in higher organisms has been documented, but the mechanisms by which they contribute to ethanol behavioral responses and the development of alcohol use disorders are not well understood. Our studies greatly extend the genetic overlap of how ethanol affects behavior from flies to mammals and provide a basis for dissecting the roles of specific biological processes and their inter-relationships in a relatively simple genetic system.