This study adds some new data to our, still incomplete, knowledge of the complexity of ER and tamoxifen pharmacology. Furthermore, it presents the first results of a potentially clinically useful antiestrogen, suitable for treatment of both tamoxifen-naive and tamoxifen-resistant ER+ breast tumors. The only available antiestrogen that has activity on these types of tumors, FaslodexR, has a different mechanism of action: receptor degradation induction. Equally important will be to compare GW5638 to aromatase inhibitors, and to study its potential use in combination with or after failure of these agents, as their target and mechanism of action are completely different. GW5638 will soon be introduced in the clinic under the name of DPC-974. The authors hypothesize that ER is a versatile transcriptional factor that exhibits different biological actions in different target cells. They also suggest that ER pharmacology is likely to depend on specific conformational changes that each individual ligand induces in its structure. These changes would expose certain peptides in the ER-ligand complex that would allow the interaction with specific coactivators, which are differently expressed in all target cells. This could also explain tamoxifen's partial agonist activity. The conformational changes induced in the ER upon exposure to either GW5638 or tamoxifen support their hypothesis.