Hypoxic-ischemic encephalopathy is a common cause of seizures in neonates. Despite the introduction of therapeutic hypothermia, seizure rates are similar to those reported in the pre-therapeutic hypothermia era. However, the seizure profile has been altered resulting in a lower overall seizure burden, shorter individual seizure durations, and seizures that are harder to detect. Electroencephalographic (EEG) monitoring is the gold standard for detecting all seizures in neonates and this is even more critical in neonates who are cooled, as they are often sedated, making seizures more difficult to detect. Several studies have shown that the majority of seizures in neonates undergoing therapeutic hypothermia remain subclinical, thus requiring EEG monitoring for diagnosis. Amplitude-integrated EEG monitoring is useful but shorter duration seizures are more likely to be missed. Evidence is emerging about the pharmacokinetic profile of routinely used antiepileptic drugs during therapeutic hypothermia and some modifications have been suggested, particularly for lidocaine use.