The molecular structures of compounds that compete for the estrogen binding site suggest that when estradiol is bound to the receptor, there is a close fit only at the A-ring end of the steroid. The most potent antagonists have phenolic rings capable of mimicking the estradiol A-ring in promoting high affinity binding to the receptor. They fail to stabilize the conformational change or molecular interaction needed to achieve hormonal response because they either lack an essential functional group (hydrogen bond donor) or they present a steric block or topological feature incompatible with transformation or interaction subsequent to the initiation of binding by the A-ring or A-ring analogues. X-Ray analyses of 12 triphenylethylene derivatives demonstrate the stability of a specific conformation that is unaffected by crystal packing forces. This conformation has a pinwheel-like orientation of phenyl rings, the direction of which is correlated with a 10 degrees twist about the central double bond and appears to depend upon the orientation of the non-phenyl substituent relative to the double bond. Empirical energy calculations are insensitive to this intramolecular structural dependence and incorrectly predict that the pinwheel of the opposite direction is of lower energy.