Breast cancer-related deaths have been on the decline ever since the application of systemic therapies. Chiefly, endocrine therapy, such as Tamoxifen, enhances the survival of estrogen receptor (ER)-positive patients. More than a decade has passed since the introduction of Tamoxifen, however, drug resistance, particularly to Tamoxifen, still remains a major challenge. It has been shown that not only does chronic Tamoxifen exposures induce resistance, but estrogen deprivation can as well. There are two Tamoxifen resistant cell lines, long term estrogen deprived (LTED) cells and cells that have acquired resistance due to long-term exposure to Tamoxifen (Tam-R). Despite having similar cytosolic pathways over-activated in Tam-R and LTED-R cells during the development of resistance, the administration of receptor tyrosine kinases (RTKs) inhibitors fail to restore Tamoxifen sensitivity in LTED-Rs. This alludes to existing differences in the underlying molecular mechanisms of resistance. Surprisingly, despite estrogen being recognized as a breast cancer stimulator; it has recently been introduced as an apoptotic inducer in unresponsive cells. Furthermore, the addition of estrogen to the media of LTED and Tam-R cells triggers cell death, perhaps is functioning as an anti-proliferative agent. In this review, we outline the molecular pathways potentially facilitating estrogen-induced apoptosis in resistant cells.