Treatment of brain tumors is increasingly informed by biomarkers that predict patient prognosis and response to therapy. While this progress represents a great opportunity for the field of neuro-oncology, it also presents significant challenges. Biomarkers are not straightforward to identify, and previously used clinical trial paradigms are poorly suited to the task of identifying treatments effective only in selected subsets of patients. Unless investigators adapt new tools and procedures that better account for the biological diversity of gliomas, future clinical trials run the dual risk of missing important treatment effects and exposing patients to interventions destined to prove ineffective for their tumors. In this article, we will review the progress made in the past decade with respect to biomarkers in neuro-oncology, address barriers to ongoing progress, and discuss clinical trial designs that may prove useful in moving neuro-oncology fully into the era of personalized medicine.