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Following primary treatment for early breast cancer, systemic adjuvant therapy is given to reduce the risk of recurrence by targeting any undetectable micrometastatic deposits. Adjuvant systemic treatment may include endocrine therapy, chemotherapy and antibody therapy, depending on the presence or absence of hormone receptors, HER2 status and the estimated risk of relapse. In recent years, an increasing number of tumor characteristics have been identified that influence the risk of relapse and the likelihood of achieving the desired outcome with a given therapy. Hence, choosing the optimum therapy for early breast cancer is becoming an increasingly complicated task. Decision tools have been developed that can be used by physicians to select the most appropriate therapy on an individual basis. Treatment recommendations are, therefore, based on available data from a large number of sources. Hormone-receptor positivity (HR+) is the primary factor when considering whether or not patients should receive adjuvant endocrine therapy. For several decades, tamoxifen has been the gold standard of endocrine therapy, and has significantly reduced recurrences and deaths among the millions of women with HR+ breast cancer worldwide. However, prolonged use of tamoxifen is associated with potentially life-threatening side effects, and resistance is a common problem. In fact, many women will experience disease relapse while on tamoxifen. In particular, the peak of early relapses that occurs in the first 2-3 years after surgery is not prevented by tamoxifen. The third-generation aromatase inhibitors (AIs), letrozole, anastrozole and exemestane, have recently been shown to significantly improve outcomes compared with tamoxifen in large, randomized, controlled trials; however, how the AIs should be incorporated into adjuvant therapy to optimize outcomes requires further investigation. Clinical differences between the AIs, and whether tumor estrogen/progesterone receptor status and HER2 overexpression affect the response to AI therapy, are among the questions that remain to be answered. Ongoing and future studies will help to address these questions and, together with improved patient and disease profiling, will help physicians to optimize adjuvant treatment for individual patients.