Triple positive breast cancer overexpress ER (estrogen receptor), PR and HER2 (human epidermal growth factor receptor 2, HER2), accounting for about 50%-60% of the HER2 positive breast cancer patients. Based on the data from clinical trials, the crosstalk between the ER signaling pathway and the HER2 signaling pathway in triple-positive breast cancer may weaken the efficacy of anti-HER2 therapy and endocrine therapy, and this feature has attracted widespread attention. Emerging evidence shows that while blocking HER2 signaling pathway, together with enhancing blocking of ER signaling pathway, such as anti-HER2 dual-targeting + endocrine therapy ± CDK4/6 inhibitors, could effectively overcome drug resistance, and improve the efficacy. Predictive biomarkers including Ki67, intrinsic subtypes, and multi-gene assay, which have the potential benefit for personalized treatment.