The human nuclear estrogen receptors (i.e., ERalpha and ERbeta), as other transcriptional factors, regulate cellular processes inducing genomic events. In addition, the binding of 17beta-estradiol to ERs induces different membrane initiating non-genomic signaling. The non-genomic effects of ER are independent of transcriptional activity of the receptor and have been attributed to membrane ERs belonging to a signaling complex localized in caveolae. Here, we postulate that S-acylation of cysteine residue(s) present in the ligand binding domain of ERalpha and ERbeta may play a critical role in the membrane caveolar localization of the receptor and in the formation of the 'steroid signalosome'.