Estrogen receptors (ER) are members of the nuclear intracellular receptors family. ER once activated by estrogen, it binds to DNA via translocating into the nucleus and regulates the activity of various genes. In about one third of the breast cancer cases, ERs are over expressed and this condition is referred to as “ER-positive”. Selective Estrogen Receptor Modulator ligands (SERMs) are involved in Endocrine therapy, which acts as ER antagonists in breast tissue. Tamoxifen is one of the most-prescribed SERM. Recent massive genome sequencing studies has revealed that presence of some point mutations in ER driving resistance undermining the efficacy of SERMs to endocrine therapy. Withaferin A (WA) – an active compound of a medicinal plant Withania Somnifera was reported to be a very effective anti-cancer agent and some of the recent studies has demonstrated that WA is capable of arresting the development of breast cancer via targeting estrogen receptor. In this scenario, the present study is aimed at understanding the molecular level interactions of ER and Tamoxifen in comparison to Withaferin A using In-silico approaches with emphasis on Withaferin A binding capability with ER in presence of point mutations which are causing de novo drug resistance to existing drugs like Tamoxifen.Copyright© Bentham Science Publishers; For any queries, please email at email@example.com.