Advances in treatment for women with advanced breast cancer (ABC) have led to improvements in survival. Although the condition remains incurable, treatment goals focus on stabilizing disease, prolonging life, and maintaining patient quality of life. Hormone receptor-positive (HR+) subtypes constitute the majority of breast cancers, and an increasing number of effective endocrine therapies are available. Although practice guidelines provide important recommendations and principles for treatment selection, the choice of specific agents from among existing options should be customized to the individual based on patient and disease characteristics, as well as the nature and duration of response to previous treatments. This review examines endocrine and endocrine-based options, including combinations with targeted agents, for HR+ and human epidermal growth factor receptor 2-negative (HER2−) ABC. It also elaborates on the factors that enter into treatment decision-making, using patient case examples to illustrate how ABC can present and the clinical issues involved in treatment selection. Case examples are included to provide evidence for the clinical scenarios of de novo HR+/HER2− ABC and progression during adjuvant treatment for early breast cancer.