To identify genomic regions involved in osmoregulation in the extremely halophilic archaeon Haloferax volcanii, we used a technique which involves hybridization of cDNAs obtained at different salinities against a cosmid library of the organism. Both low and high salt concentrations trigger differential expression; however, adaptation to low salinities seems to elicit a wider response. The presence of a large domain within the largest of the megaplasmids with a strong response to low salt concentrations is noteworthy.