Seizures are more common in the neonatal period than any other time in the human lifespan. A high index of suspicion for seizures should be maintained for infants who present with encephalopathy soon after birth, have had a stroke, central nervous system (CNS) infection or intracranial hemorrhage or have a genetic or metabolic condition associated with CNS malformations. Complicating the matter, most neonatal seizures lack a clinical correlate with only subtle autonomic changes and often no clinical indication at all. Over the last three decades, several tools have been developed to enhance the detection and treatment of neonatal seizures. The use of electroencephalography (EEG) and the later development of amplitude-integrated EEG (aEEG), allows for Neurologists and non-Neurologists alike, to significantly increase the sensitivity of seizure detection. When applied to the appropriate clinical setting, time to diagnosis and start of therapy is greatly reduced. Phenobarbital maintains the status of first-line therapy in worldwide use. However, newer anti-epileptic agents such as, levetiracetam, bumetanide, and topiramate are increasingly being applied to the neonatal population, offering the potential for seizure treatment with a significantly better side-effect profile. Seizures in premature infants, continue to confound clinicians and researchers alike. Though the apparent seizure burden is significant and there is an association between seizures and adverse outcomes, the two are not cleanly correlated. Compounding the issue, GABA-ergic anti-epileptic drugs are not only less effective in this age group due to reversed neuronal ion gradients but may cause harm. Selecting an appropriate treatment group remains a challenge.