All medications have some adverse effects, ranging from mild to acute and serious or chronic. Antiepileptic drugs (AEDs) differ in the type and severity of adverse effects, mostly during initiation and early treatment. Some concerns are related to pharmacodynamic tolerance often affected by the dose and rate of initiation, while other concerns are idiosyncratic responses to the drug (rare and not predictable). Thus, lack of tolerability is a common reason for changing medication, quantified in studies as treatment retention. Although adverse effects can occur with all AEDs, and CNS effects are most prevalent, selected effects are hallmarks of specific drugs. The failure of an AED regimen may be the result of unacceptable adverse effects (intolerance), inadequate seizure control (inefficacy) or a combination of both. Although some diminution in adverse effects is typical when a drug is used in monotherapy, the potential for most issues remains if they are dose-related or idiosyncratic. This article describes three categories of prevalent adverse effects (CNS, behavioral and general medical issues) comparing profiles of second- and third-generation AEDs.