The estrogen-dependent nature of breast cancer is the fundamental basis for endocrine therapy. The presence of estrogen receptor (ER), the therapeutic target of endocrine therapy, is a prerequisite for this therapeutic approach. However, estrogen-independent growth often exists de novo at diagnosis or develops during the course of endocrine therapy. Therefore ER alone is insufficient in predicting endocrine therapy efficacy. Several RNA-based multigene assays are now available in clinical practice to assess distant recurrence risk, with majority of these assays evaluated in patients treated with 5 years of adjuvant endocrine therapy. While MammaPrint and Oncotype Dx are most predictive of recurrence risk within the first 5 years of diagnosis, Prosigna, Breast Cancer Index (BCI), and EndoPredict Clin have also demonstrated utility in predicting late recurrence. In addition, PAM50, or Prosigna, provides further biological insights by classifying breast cancers into intrinsic molecular subtypes. Additional strategies are under investigation in prospective clinical trials to differentiate endocrine sensitive and resistant tumors and include on-treatment Ki-67 and Preoperative Endocrine Prognostic Index (PEPI) score in the setting of neoadjuvant endocrine therapy. These biomarkers have become important tools in clinical practice for the identification of low risk patients for whom chemotherapy could be avoided. However, there is much work ahead toward the development of a molecular classification that informs the biology and novel therapeutic targets in high-risk disease as chemotherapy has only modest benefit in this population. The recognition of somatic mutations and their relationship to endocrine therapy responsiveness opens important opportunities toward this goal.