Hypoxic-ischemic encephalopathy [HIE] represents the most common acquired pathology associated with neonatal seizures. HIE-associated neonatal seizures are often difficult to control, due to their refractoriness to traditional anti-seizure agents. Developmentally regulated chloride gradients during early development make the neonatal brain more seizure-susceptible by depolarizing GABAAR-mediated currents, and therefore hindering inhibition by conventional anti-seizure drugs such as phenobarbital [PB] and benzodiazepines. Pharmaco-modulation of chloride co-transporters has become a current field of research in treating refractory neonatal seizures, and the basis of two clinical trials [NCT01434225; NCT00380531]. However, the recent termination of NEMO study [NCT01434225] on bumetanide, an NKCC1 antagonist, suggests that clinical utilization of bumetanide as an adjunct to treat neonatal seizures with PB may not be a viable option. Hence, re-evaluation of bumetanide as an adjunct through pre-clinical studies is warranted. Additionally, the model-specific variability in the efficacy of bumetanide in the pre-clinical models of neonatal seizures highlights the differential consequences of insults used to induce seizures in each pre-clinical model as worth exploration. Injury itself can significantly alter the function of chloride co-transporters, and therefore the efficacy of anti-seizure agents that follow.