Estrogen-deprivation strategies with aromatase inhibitors are superior to tamoxifen in the adjuvant, neoadjuvant and advanced breast-cancer settings in postmenopausal patients. Short-term hormonal resistance especially in the HER2-positive patient population, however, is a significant issue with these endocrine agents. The authors discuss the progress made in our understanding of resistance to endocrine therapy, and provide insights regarding the management of patients with hormone receptor-positive/HER2-positive advanced breast cancer.