Despite estrogen receptor-alpha (ERα) being one of the earliest known and best validated protein targets for cancer therapeutics, our incomplete knowledge about its full molecular structure, mechanism of action, and multiple roles in intracellular signaling and transcriptional control of both normal organ development and malignant tumor growth continues to foster an industry of basic and translational research on this nuclear receptor system [1, 2]. The gene discussed is ESR1; the disease is cancer.