Seizures in the idiopathic generalized epilepsies (IGEs) usually remit completely with antiepileptic drugs (AEDs). Occasionally, however, they may be aggravated by AEDs. Before attributing exacerbation of seizures to an AED, alternative explanations need to be excluded. These include natural fluctuation of seizures, irregular compliance, maladjustment to the disease, comorbid illness, and development of tolerance. Aggravation may be due to a paradoxical reaction or drug-induced encephalopathy, sedative effects, or inappropriate use of a drug; and this need to be established, as it will guide management. An important caveat is that most data on aggravation of generalized seizures are based on anecdotal case reports or case series. Whether considering efficacy or aggravation, the interpretation of data from uncontrolled studies and case reports must be treated with caution. In practice, despite the fact that clear evidence is lacking, the possibility of seizure aggravation must be considered when treating people with IGEs. Predictive factors for seizure aggravation in a particular patient with a specific drug are yet to be fully defined. It is paramount to classify seizure type correctly in all patients. If this is not possible, a broad-spectrum AED should be used. Drugs that modulate Na+-channels and GABAergic drugs seem to be more prone to aggravating seizures, and therefore are best avoided in the initial management of IGE. Further studies are required to elucidate this phenomenon in full. It is interesting to speculate that paradoxical responses to AEDs may have pharmacogenetic value, serving as tools for a more precise and useful characterization of the epilepsies.