Breast cancer (BC) is the most common cancer in women. 1 in 8 women will be diagnosed with breast cancer in their lifetime. The majority of breast cancers are hormone receptor positive (HR+), expressing estrogen receptors (ER) and/or progesterone receptors. The mainstay of treating HR+ breast cancers are anti-estrogen therapies: selective estrogen receptor modulators, aromatase inhibitors, and/or selective estrogen receptor degraders. Studying the mechanisms of resistance in HR+ BC has led to the development of new classes of therapies targeting the downstream molecules of the estrogen receptor, cyclin dependent kinase 4/6 inhibitors, and other pathways such as Phosphoinositide 3 kinase, AKT, and mTOR inhibitors. These next generation therapies are currently used in the metastatic setting where they improve quality of life, overall survival, and delay initiation of chemotherapy. This chapter presents five HR+ BC cases to demonstrate how therapy can be personalized.