Estrogen and estrogen receptor-alpha (ER) signaling are important factors in the pathogenesis and treatment of ER-positive breast cancers. Therefore targeted therapies against ER, known as endocrine therapies, are widely used in the treatment of ER-positive breast cancers. While these therapies have shown great success, de novo and acquired resistance are common. The approach to the problem of endocrine therapy resistance is twofold: identify the mechanisms of resistance and develop alternative treatments to overcome these mechanisms. This review focuses on the progress and integration of these two aspects of resolving endocrine therapy resistance in ER-positive breast cancer patients.