Tumor-associated epilepsy is the most common presenting symptom in patients diagnosed with diffuse gliomas. Recent evidence illustrates the requirement of synaptic activity to drive glioma proliferation and invasion. Class 1, 2, and 3 evidence is limited regarding the use of antiepileptic drugs (AEDs) as antitumor therapy in combination with chemotherapy. Furthermore, no central mechanism has emerged as the most targetable. The optimal timing of AED regimen remains unknown. Targeting aberrant neuronal activity is a promising avenue for glioma treatment. Clinical biomarkers may aid in identifying patients most likely to benefit from AEDs. Quality evidence is needed to guide treatment decisions.