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Patients with high-risk early-stage estrogen receptor-positive breast cancer are usually treated with chemotherapy and adjuvant endocrine therapy. The modalities and duration of this endocrine therapy are controversial, though five years of treatment is considered the standard of care for the entire patient population. Given that the risk of recurrence remains high even after ten to fifteen years of follow-up, several treatment options are available. Extended endocrine therapy (beyond five years) is the preferred treatment option. Adding targeted agents also appears to be viable: CDK4/6 inhibitors may become the new standard of care and PARP inhibitors have been shown to increase overall survival of patients with pathogenic or likely pathogenic germline BRCA1 or BRCA2 variants. However, other treatments must be developed and genomic tools implemented to continue improving survival for this patient population who remain at high risk of relapse.