Breast cancers that are positive for hormone receptor but negative for human epidermal growth factor receptor 2 (abbreviated as HR+/HER2-) account for approximately 60% of total cases. Targeting estrogen signaling is one of the most important therapeutic strategies for HR+/HER2- breast cancer. However, the management of endocrine-resistant HR+/HER2- breast cancer remains a difficult issue in clinical practice. Previous multi-omic analysis and translational research have identified the mechanisms underlying endocrine-resistance including genomic alteration and abnormal epigenetic modification. To overcome endocrine-resistance, we have established a comprehensive and coherent therapeutic strategy.  In addition, several novel therapies have shown promising efficacy in previous clinical trials and will emerge as alternative options for targeting endocrine-resistant HR+/HER2- breast cancer. In this review, we will introduce the mechanisms of endocrine-resistance, explain the current therapeutic strategy for endocrine-resistant HR+/HER2- breast cancer and discuss the possible targeted therapies in the future.