For almost three decades, tamoxifen has been the mainstay of hormonal therapy in breast cancer patients, but now the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, are emerging as potential alternatives, associating greater clinical efficacy with a more favourable overall safety profile than tamoxifen. AIs are associated with a lower incidence of thromboembolic events and vaginal bleeding compared with tamoxifen, although they are known to affect bone turnover and possibly lipid metabolism. As the available AIs have similar efficacy, it is likely that safety and tolerability profiles will have an impact on agent selection in clinical practice. Therefore, it is important that differences in the safety profiles of the third-generation AIs are understood.