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The paucity of evidence\u2010based treatment guidelines, coupled with a rudimentary understanding of disease pathogenesis, has made the current treatment of neonatal seizures empiric and often ineffective, highlighting the need for novel therapies. Key developmental differences in \u03b3\u2010aminobutyric acid (<jats:styled-content style=\"fixed-case\">GABA)<\/jats:styled-content>ergic neurotransmission between the immature and mature brain, and trauma\u2010induced alterations in the function of the cation\u2010chloride cotransporters (<jats:styled-content style=\"fixed-case\">CCC<\/jats:styled-content>s) <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1 and <jats:styled-content style=\"fixed-case\">KCC<\/jats:styled-content>2, probably contribute to the poor efficacy of standard antiepileptic drugs used in the treatment of neonatal seizures. Although <jats:styled-content style=\"fixed-case\">CCC<\/jats:styled-content>s are attractive drug targets, bumetanide and other existing <jats:styled-content style=\"fixed-case\">CCC<\/jats:styled-content> inhibitors are suboptimal because of pharmacokinetic constraints and lack of target specificity. Newer approaches including isoform\u2010specific <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>1 inhibitors with increased central nervous system penetration, and direct and indirect strategies to enhance <jats:styled-content style=\"fixed-case\">KCC<\/jats:styled-content>2\u2010mediated neuronal chloride extrusion, might allow therapeutic modulation of the <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>ergic system for neonatal seizure treatment.<\/jats:p><jats:p>A PowerPoint slide summarizing this article is available for download in the Supporting Information section <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" 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