In Caenorhabditis elegans (C. elegans) the gene unc-1 controls anesthetic sensitivity and normal locomotion. The protein UNC-1 is a close homologue of the mammalian protein stomatin and is expressed primarily in the nervous system. Genetic studies in C. elegans have shown that the UNC-1 protein interacts with a sodium channel subunit, UNC-8. In humans, absence of stomatin is associated with abnormal sodium and potassium levels in red blood cells. Stomatin has also been postulated to participate in the formation of lipid rafts, which are membrane microdomains associated with protein complexes, cholesterol and sphingolipids. In this report we isolated a low density, detergent resistant fraction from cell membranes of C. elegans. This fraction contains cholesterol, sphingolipids and protein consistent with their identification as lipid rafts. We then probed Western blots of protein from the rafts and found that the UNC-1 protein is almost totally restricted to this fraction. The UNC-8 protein is also found in rafts and co-immunoprecipitates UNC-1. A second stomatin-like protein, UNC-24, also affects anesthetic sensitivity, is found in lipid rafts and regulates UNC-1 distribution. Mutations in the unc-24 gene alter the distribution of UNC-1 in lipid rafts. Each of these mutations alters anesthetic sensitivity in C. elegans. Since lipid rafts contain many of the putative targets of volatile anesthetics, they may represent a novel class of targets for volatile anesthetics.