Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), a biologically active constituent of marijuana, possesses a wide variety of pharmacological and toxicological effects ( e.g. , analgesia, hypotension, reduction of inflammation, and anti-cancer effects). Among Δ⁹-THC’s biological activities, its recognized anti-estrogenic activity has been the subject of investigations. Since Δ⁹-THC is used as both a drug of abuse (marijuana) and as a preventive therapeutic to treat pain and nausea in cancer patients undergoing chemotherapy in the United States and other countries (synthesized Δ⁹-THC; dronabinol), it is important to investigate the mechanistic basis underlying the anti-estrogenic activity of Δ⁹-THC. Since Δ⁹-THC has “no” binding potential for estrogen receptor α (ERα) which can be activated by estrogen (E2), the question of how Δ⁹-THC exerts its inhibitory effect on ERα is not resolved. We have recently reported that ERβ, a second type of ER, is involved in the Δ⁹-THC abrogation of E2/ERα-mediated transcriptional activity. Here we discuss the possible mechanism(s) of the Δ⁹-THC-mediated disruption of E2/ERα signaling by presenting our recent findings as well.