Breast cancer (BC) is the most commonly diagnosed cancer in women, constituting one-third of all cancers in women, and it is the second leading cause of cancer-related deaths in the United States. Anti-estrogen therapies, such as selective estrogen receptor modulators, significantly improve survival in estrogen receptor-positive (ER+) BC patients, which represents about 70% of cases. However, about 60% of patients inevitably experience intrinsic or acquired resistance to anti-estrogen therapies, representing a major clinical problem that leads to relapse, metastasis, and patient deaths. The resistance mechanisms involve mutations of the direct targets of anti-estrogen therapies, compensatory survival pathways, as well as alterations in the expression of non-coding RNAs (e.g., microRNA) that regulate the activity of survival and signaling pathways. Although cyclin-dependent kinase 4/6 and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors have significantly improved survival, the efficacy of these therapies alone and in combination with anti-estrogen therapy for advanced ER+ BC, are not curative in advanced and metastatic disease. Therefore, understanding the molecular mechanisms causing treatment resistance is critical for developing highly effective therapies and improving patient survival. This review focuses on the key mechanisms that contribute to anti-estrogen therapy resistance and potential new treatment strategies alone and in combination with anti-estrogen drugs to improve the survival of BC patients.