The human epidermal growth factor receptor 2 (HER2) is overexpressed in 13–22% of breast cancers (BC). Approximately 60–70% of HER2+ BC co-express hormone receptors (HRs). HR/HER2 co-expression modulates response to both anti-HER2–directed and endocrine therapy due to “crosstalk” between the estrogen receptor (ER) and HER2 pathways. Combined HER2/ER blockade may be an effective treatment strategy for patients with HR+/HER2+ BC in the appropriate clinical setting(s). In this review, we provide an overview of crosstalk between the ER and HER2 pathways, summarize data from recently published and ongoing clinical trials, and discuss clinical implications for targeted treatment of HR+/HER2+ BC.