Seizures are a common complication in patients with primary brain tumors or brain metastases that require treatment with antiepileptic drugs (AEDs). However, because many AEDs and chemotherapeutics share common metabolic pathways via the hepatic cytochrome P450 (CYP) isoenzymes, there is potential for drug interactions. Phenytoin, carbamazepine, and phenobarbital are potent enzyme-inducing AEDs (EIAEDs) that can cause a decrease in the serum concentration of chemotherapeutics, potentially compromising antitumor activity. Likewise, chemotherapeutics can alter the pharmacokinetics of EIAEDs, resulting in decreased seizure control. Other agents, such as valproic acid, are enzyme-inhibiting AEDs that can impede the metabolism of other drugs, potentially increasing the serum concentration of chemotherapeutics. Therefore, patients receiving valproic acid with concomitant chemotherapy should be monitored closely. A new generation of AEDs that are not metabolized by CYP isoenzymes is currently being developed. Of these, gabapentin and levetiracetam show the most promise in treating epileptic seizures in patients with brain tumors. Interactions between these newer AEDs and chemotherapeutic agents have not been reported. In summary, the potential interactions between AEDs and chemotherapy should be anticipated and appropriate proactive adjustments implemented. Future studies will define the role of newer AEDs in the treatment of patients with primary brain tumors.