Many patients with epilepsy are on lifelong therapy with antiepileptic drugs (AEDs), and AEDs are used for other conditions such as mood stabilization and headache prophylaxis. These drugs have high potential for clinically significant interaction with nonepilepsy drugs. Interactions occur largely through altered pharmacokinetics. One drug may increase the hepatic clearance of another, leading to attenuated efficacy of the affected drug. Alternatively, inhibition of liver metabolism by one drug can cause acute toxicity by reducing clearance of another drug. To identify potential drug interactions before they lead to toxicity or therapy failure, the treating clinician should combine knowledge of the patient’s overall history with a general knowledge of comorbid conditions in which significant interactions involving AEDs are most likely to occur. Treatments susceptible to interactions include anticoagulants, antiarrhythmics, antibiotics, antiretroviral drugs, immunosuppressives, antineoplastics, and contraceptives. Therefore, it is important to obtain periodically a thorough history of medical problems, use of medications or herbal remedies, and adverse effects of medications. Physicians managing epilepsy patients should also strive to avoid potential drug interactions by favoring low-interaction AEDs in patients taking many other types of drugs. There is quite a large degree of patient heterogeneity in the extent of any given interaction between an AED and another drug. Indeed, some groups of patients may have different susceptibilities to such interactions because of genetic and environmental influences on drug metabolism. Effective treatment with AEDs should include attention to drug interactions.