HER2-positive tumors have a worse prognosis than HER2-negative cancers. Although the standard treatment for HER2-positive metastatic breast cancer is chemotherapy and trastuzumab, the combination of aromatase inhibitors with anti-HER2 therapies has become an available strategy in patients with HER2-positive and hormone receptor-positive tumors. However, although this new treatment option is more effective than hormone therapy alone, it has not been compared with the standard chemotherapy and trastuzumab-based regimens. In fact, the activity observed in randomized clinical trials with chemotherapy and anti-HER2 therapies seems to be higher than that observed with aromatase inhibitors and trastuzumab-based or lapatinib-based therapies. In this article, we highlight the importance of considering chemotherapy and anti-HER2 therapy as the standard of care in HER2-positive and hormone receptor-positive tumors.