Knowledge about the comparative safety and efficacy of standard and new antiepileptic drugs (AEDs) is limited. Medications are selected on the basis of seizure type and epilepsy syndrome, adverse effect profiles, and cost. However, there are few data comparing the efficacy of the new AEDs for the treatment of recent-onset versus refractory partial seizures, simple versus complex partial seizures, frontal versus temporal lobe seizures, or other relevant clinical types. Few studies compare new AEDs. The next best approach has been the use of meta-analyses and compilation of data from clinical trials, which allow interstudy comparisons to define broad and rough comparative estimates. These analyses, however, do not define clear differences in the safety and efficacy of the new AEDs because of differences in study populations. The new AEDs have expanded our arsenal against seizures. As a group, they have favorable safety and efficacy profiles. The challenge is to define the differences in terms of clinical significance.