Tamoxifen has been the gold standard adjuvant therapy for the treatment of postmenopausal women with hormone-receptor-positive (HR+) early breast cancer for many years. Tamoxifen treatment is limited to 5 years because of the development of de novo and acquired resistance, and an ongoing risk of adverse events, including endometrial cancer, thromboembolic events, and gynecological symptoms with long-term use. The third-generation aromatase inhibitors (AIs), letrozole, anastrozole, and exemestane, are displacing tamoxifen as the first-choice therapy for HR+ early breast cancer, and are now recommended as the preferred therapy by national and international guidelines. Recent randomized trials have demonstrated that the AIs are more effective than tamoxifen in preventing disease recurrence when used in substitution and sequential strategies in the early adjuvant setting, and letrozole has been shown to be more effective than placebo in the extended adjuvant setting (after 5 years of tamoxifen therapy). Trial safety data show that the overall tolerability of AIs is similar to that of tamoxifen, with adverse events being predictably characteristic of estrogen deprivation; however, some important differences in adverse event profiles between tamoxifen and the AIs have been demonstrated. In addition to antiestrogenic effects, tamoxifen acts as an estrogen agonist in some tissues, which can lead to serious side effects not associated with the AIs, which prevent estrogen biosynthesis. A lower incidence of gynecological and thromboembolic events is observed in patients taking AIs, and fewer cases of endometrial cancer are seen compared with tamoxifen. Adverse events that are more frequent with adjuvant AI therapy compared with tamoxifen include arthralgia and myalgia, bone loss, and effects on the cardiovascular system and blood lipids. The effects of AIs on bone are predictable and may be easily managed, where necessary, with bisphosphonates. Studies examining the effects of AIs on the cardiovascular system and lipid profiles, including in the extended adjuvant setting, suggest that these adverse events may be due to the absence of a protective effect of tamoxifen rather than true AI toxicity. Further studies are required to determine the long-term safety of AI therapy in postmenopausal women with HR+ early breast cancer.