Estrogen receptors (ERα and ERβ) belong to the nuclear receptor superfamily. They mediate the effects of estrogens by binding (as homodimers or heterodimers) either directly to DNA at their estrogen-response elements (EREs) or by protein-protein interactions with other transcription factors (i.e., AP-1, NF-kβ) bound to their cognate DNA sequences, thus regulating the transcription of estrogen-responsive genes . The ER mediates estrogenic activity in a variety of organs, including those in the reproductive, cardiovascular, immune and central nervous systems. Estrogen provides neuroprotection against neurodegenerative diseases, including Parkinsons disease. Its effects may stem from interactions with neurons, astrocytes and microglia. Human breast cancer cell lines expressing the (ERα), all-trans-retinoic acid (ATRA) receptor α (RARα) and cellular retinoic acid binding protein II (CRABPII) genes are sensitive to ATRA-mediated growth inhibition, as well. Several naturally found polyphenols like, flavonoids, phytoestrogens, etc., interact with the ERα and ERβ, exhibit estrogenic/antiestrogenic activities, and may play protective roles in cancer, inflammation, heart disease and osteoporosis, etc., and other disease conditions. These molecules are considered "natural" selective estrogen receptor modulators (SERMs) and their use as an alternative for hormone therapy during menopause has recently expanded . This review reports about some important and promising molecules from natural resources, which modulate the ER expression and ultimately cause modulations in breast cancer and related clinical problems. The results discussed in this review are some from the works from our group and also from other groups around the globe.