Simple SummaryMetastasis is the root cause of cancer death, responsible for roughly 90% of all cancer-related fatalities. Therefore, treating metastatic cancer is essential for optimal clinical management of these patients. Although there is currently no effective treatment for metastatic breast cancer, high-throughput approaches have identified novel molecules that are critical to tumor growth and metastasis in recent years. Novel therapies that target these molecules, such as immunotherapy, have been evaluated in both preclinical and clinical settings and have proven to be very promising in prolonging survival and relieving symptoms of metastatic disease, thereby enhancing the quality of life of patients. Due to the high intertumoral and intratumoral heterogeneity of cancer, the development of subtype-specific therapeutics and the use of combination treatments to simultaneously target multiple oncogenic signaling pathways may overcome drug resistance and achieve better clinical outcome for metastatic breast cancer.AbstractBreast cancer is now the most common cancer worldwide, and it is also the main cause of cancer-related death in women. Survival rates for female breast cancer have significantly improved due to early diagnosis and better treatment. Nevertheless, for patients with advanced or metastatic breast cancer, the survival rate is still low, reflecting a need for the development of new therapies. Mechanistic insights into metastatic breast cancer have provided excellent opportunities for developing novel therapeutic strategies. Although high-throughput approaches have identified several therapeutic targets in metastatic disease, some subtypes such as triple-negative breast cancer do not yet have an apparent tumor-specific receptor or pathway to target. Therefore, exploring new druggable targets in metastatic disease is a high clinical priority. In this review, we summarize the emerging intrinsic therapeutic targets for metastatic breast cancer, including cyclin D-dependent kinases CDK4 and CDK6, the PI3K/AKT/mTOR pathway, the insulin/IGF1R pathway, the EGFR/HER family, the JAK/STAT pathway, poly(ADP-ribose) polymerases (PARP), TROP-2, Src kinases, histone modification enzymes, activated growth factor receptors, androgen receptors, breast cancer stem cells, matrix metalloproteinases, and immune checkpoint proteins. We also review the latest development in breast cancer immunotherapy. Drugs that target these molecules/pathways are either already FDA-approved or currently being tested in clinical trials.