Endocrine therapy remains a mainstay in the treatment of hormone-sensitive metastatic breast cancer. Nevertheless, acquired resistance to endocrine therapy is an important clinical problem. Understanding the mechanisms of resistance is fundamental in order to develop new therapeutic strategies such as mTOR inhibition through everolimus. Its efficacy in association with endocrine therapy has been shown in two randomized trials. However, the addition of everolimus to endocrine therapy is accompanied by a significant increase in potentially severe side effects. Identifying and adequately addressing these side effects is crucial to decrease toxicity of these new therapies.