en Health Services, Quality of Life and Outcomes Review Article In 1980, tamoxifen was introduced as an effective adjuvant endocrine therapy for breast cancer, resulting in a significant increase in overall survival. Nevertheless, the development of acquired resistance limited the efficacy of tamoxifen therapy. Several molecular mechanisms have been proposed to explain the probable process of tamoxifen resistance. In vitro studies have suggested that alterations in the expression of cytoplasmic growth cascades such as insulin-like growth factor receptor (IGFR) and epidermal growth factor receptor (EGFR) along with associated downstream signaling pathways such as ERK1, ERK2, and ERK6 are the main cause of resistance to tamoxifen. In this review, we investigated the role of estrogen receptor-α (ER-α), EGFR, IGFR, and their downstream signaling pathways in tamoxifen resistance. The present study attempted to find out possible culprits of tamoxifen resistance to improve treatment efficacy in breast cancer patients. Breast Neoplasms, Estrogen Receptor alpha, Epidermal Growth Factor, Receptor, Insulin-Like Growth Factor, Receptor, Signal Pathways, Tamoxifen 6 16 http://mcijournal.com/browse.php?a_code=A-10-32-5&slc_lang=en&sid=1 Sepideh Mansouri 10031947532846003663 10031947532846003663 No Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran Tannaz Samadi 10031947532846003664 10031947532846003664 No Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran Azin Teymourzadeh 10031947532846003665 10031947532846003665 No Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran Keivan Majidzadeh-A 10031947532846003666 10031947532846003666 No Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran Leila Farahmand l.farahmand@acecr.ac.ir 10031947532846003667 10031947532846003667 Yes Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran