Management of advanced prostate cancer remains complex, with substantial changes in treatment options emerging in recent years having implications for treatment selection and sequencing. Recognition of the importance of androgen signaling has led to life-prolonging treatments, as well as “liquid biopsy” techniques to guide these treatments in some settings. Therapies that target estrogen receptor signaling are efficacious but infrequently used options for treatment of castration-resistant prostate cancer. It is possible that nuances of estrogen receptor (ER) signaling, or selective modulation of ER signaling, might favorably influence outcomes in castration-resistant prostate cancer. Expression of ERs and their variants has been investigated in other cancers such as breast. Constitutively activating gene alterations can potentially lead to ER activation and subsequently promote cancer progression. The identification of these aberrations may help identify cancer phenotypes that are susceptible or resistant to therapies involved in ER signaling. This review outlines the current literature regarding ER signaling in prostate cancer, and provides background for exploration of potentially useful ER signaling biomarkers in advanced prostate cancer.