Selecting an antiepileptic drug (AED) for treatment of seizures is daunting because there are now 20 from which to choose. Following simple principles allows a systematic approach to drug selection. Efficacy studies provide limited information. For initial monotherapy of partial seizures, high-level evidence exists for the efficacy of lamotrigine, carbamazepine, oxcarbazepine, and topiramate. For initial monotherapy of generalized seizures, high-level evidence is available for valproate, lamotrigine, topiramate, and oxcarbazepine. For initial monotherapy of absence seizures, high-level evidence exists for valproate, lamotrigine, and ethosaximide. All second-generation AEDs have efficacy as adjunctive therapy for partial seizures. AEDs are often useful for comorbid conditions or have properties that should be avoided in some groups. Thus, AEDs should usually be selected on the basis of comorbid conditions, including depression, migraine, chronic pain, obesity, and nephrolithiasis, or patient characteristics, especially for women of childbearing potential and older adults.