Pharmacologic treatment options for neonatal seizures have expanded over the past 2 decades, and there is no consensus on optimal treatment strategy. We systematically reviewed the published literature to determine which medication(s) are most effective for treating neonatal seizures, by retrieving trials and observational investigations via PubMed (through August 2011) that focused on pharmacological seizure treatment of neonates (≤ 28 days old) and utilized continuous or amplitude-integrated EEG to confirm seizure diagnosis and cessation. Our search identified 557 initial articles and 14 additional studies after reference reviews, with 16 meeting inclusion criteria. Of these, 2 were randomized trials and only 3 additional investigations included comparison groups. We found limited evidence regarding the best pharmacologic treatment for neonatal seizures, but were able to devise a treatment algorithm from available data. These findings have the potential to serve as a clinical reference and to inform the design of comparative effectiveness investigations for neonatal antiepileptics.