The selective estrogen receptor modulators (SERMs) are synthetic pharmaceuticals, the relative agonist and antagonist activities of which are not equivalent in all cells. Their discovery has raised the possibility that endogenous small molecules might exist that have similar properties and could have important physiological roles. In support of this hypothesis is the recent demonstration that the oxysterol 27-hydroxycholesterol (27HC) interacts with and modulates the transcriptional activity of both estrogen receptor (ER) subtypes and that the relative agonist and antagonist activity of 27HC is influenced by both cell and promoter context. Although there is limited information available on the role of 27HC in classical estrogen-responsive tissues, that which is available in animal models of cardiovascular disease and cellular models of breast cancer support a role for this ligand in ER signaling. These results provide an interesting potential link between cholesterol (and cholesterol metabolism) and ER function, the physiological and pathological importance of which remains to be determined.