Abstract: Hypoxic-ischemic encephalopathy (HIE) has an incidence of 1–3 in 1000 term births in high-income countries (Zhou et al., 2020). The standard treatment for these infants is therapeutic hypothermia. Although therapeutic hypothermia significantly reduces the risk of death and disability for infants with HIE, it is still only partially protective as up to 45% of infants still develop disability despite treatment (Zhou et al., 2020). The current therapeutic hypothermia protocol is optimal for widespread use in infants with moderate to severe HIE. However, it is possible that a more tailored approach for individual babies, including stratification of the cooling regimen for the severity of HIE and the identification of reliable biomarkers to guide treatment, may improve efficacy in the future. Current research efforts are now focused on finding add-on treatments to hypothermia that can provide additive neuroprotection (Zhou et al., 2020). This endeavor has proven to be very difficult, as many therapeutic agents have been tested in preclinical and clinical studies, but have shown a lack of additive neuroprotection to therapeutic hypothermia (Zhou et al., 2020). Therefore, a better understanding of the mechanisms of injury that are not targeted by therapeutic hypothermia is needed, in order to find the appropriate add-on treatment that has complementary mechanisms of action.