Everolimus (an mTOR inhibitor) has recently advanced the treatment of hormone receptor-positive and HER2-negative (HR+/HER2-) metastatic breast cancer by approximately doubling progression-free survival when combined with endocrine (hormonal) therapy. Development of a predictive diagnostic combining everolimus with endocrine therapy for metastatic HR+/HER2- breast cancer is clinically important. There are already many current treatment options for these patients (endocrine therapies, chemotherapies, endocrine therapy with everolimus), and other novel targeted therapies are advancing in clinical development. Also, everolimus has significant toxicity in some patients. Therefore, we anticipate clinical need for diagnostics to prioritize treatments that maximize benefit within each class of therapies and avoid the opportunity cost and unnecessary toxicities of futile treatments.