Drugs targeting the estrogen signaling pathway through the selective estrogen receptor modulator (SERM) (e.g., tamoxifen, raloxifene), the estrogen receptor (ER) antagonists (e.g., fulvestrant) and, the aromatase inhibitors, including the reversible nonsteroidal agents (e.g., letrozole, anastrozole), or the irreversible steroidal inactivator (e.g., exemestane), has been used for decades to treat ER positive breast cancer (Figure 1) [4]. The gene discussed is ESR1; the disease is breast cancer.