Breast cancer is not one homogeneous disease; it is a heterogeneous cancer with remarkable genomic variation and variable risk for systemic spread, time to recurrence, and response to treatment. Although it is increasingly clear that a substantial proportion of newly diagnosed patients with breast cancer carry only minimal risk of developing metastatic disease, our inability to accurately prognosticate leads to systemic overtreatment. The recent introduction of multigene predictors for baseline risk assessment and treatment response in breast cancer subsets heralds the beginning of personalized cancer care and the transition to precision medicine. At the same time, rapid clinical adoption of these predictors illustrates the voracious unmet need for better and more finely tuned prognostic and predictive tools. Recent advances in clinical trial designs have enabled the testing of novel agents in combination with standard therapy in the neoadjuvant setting, with a goal of identifying the specific biomarker-drug pairs that should be advanced for confirmatory trials and accelerated approval on the basis of response to therapy.