Steroid hormones can act as chemical messengers in a wide range of species and target tissues to produce both slow genomic responses, and rapid non-genomic responses. Although it is clear that genomic responses to steroid hormones are mediated by the formation of a complex of the hormone and its cognate steroid-hormone nuclear receptor, new evidence indicates that rapid responses are mediated by a variety of receptor types associated with the plasma membrane or its caveolae components, potentially including a membrane-associated nuclear receptor. This review summarizes our current knowledge of membrane-associated steroid receptors, as well as details of structure–function relationships between steroid hormones and the ligand-binding domains of their nuclear and membrane-associated receptors. Furthermore, a new receptor conformational ensemble model is presented that suggests how the same receptor could produce both rapid and genomic responses. It is apparent that there is a cornucopia of new drug development opportunities in these areas.