Different lines of evidence converged toward the notion that breast tumors have a mesenchymal “heart.” However, for decades the major efforts in the fight against breast cancer have searched for diagnostic parameters and therapeutic targets directly or indirectly related to the epithelial phenotype, such as HER-2, estrogen receptors, progesterone receptors, anatomical architecture of the gland, and ductal or luminal morphology. The gene discussed is ESR1; the disease is breast cancer.