The molecular mechanisms occurring in the nervous system that underlie behavioral responses to ethanol remain poorly understood. Here, we report that molecular requirements for two of these responses, initial sensitivity and the development of rapid tolerance, comap to the same small set of neurons. We show that null homer mutant flies exhibit both increased sensitivity to the sedative effects of ethanol and failure to develop normal levels of rapid tolerance. Both the sensitivity and rapid tolerance phenotypes of the homer mutants are rescued by the expression of wild-type homer in a subset of neurons that include the ellipsoid body. Thus, some of the molecular- and systems-level requirements for these two behavioral responses to ethanol are identical.