Hormone receptor-positive HER2-positive (HR+/HER2+) metastatic breast cancer (MBC) is a unique subtype of breast cancer. Most current guidelines recommend that combination regimens based on anti-HER2 therapy should be used as first-line treatment for HER2+ MBC, irrespective of HR status. Endocrine therapy can be applied as maintenance therapy for patients who are intolerant to chemotherapy or post-chemotherapy. Increasing evidence suggests that complex molecular crosstalk between HR and HER2 pathways may affect the sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ breast cancer. Recent research and clinical trials have revealed that a combination of endocrine therapy and anti-HER2 approaches without chemotherapy provides along-term disease control for some patients, but the challenge lies in how to accurately identify the subsets of patients who can benefit from such a de-chemotherapy treatment strategy. In this review, we aim to summarize the results of preclinical and clinical studies in HR+/HER2+ MBC and discuss the possibility of sparing chemotherapy in this subgroup of patients.