Hypoxic-ischemic (HI) insults before and during birth, secondary to events such as placental abruption or umbilical cord occlusion, are a significant contributor to neonatal brain injury (hypoxic-ischemic encephalopathy; HIE). [1,2] The preterm newborn is at greater risk of HIE. [1] In contrast to an overall incidence of 1-3/1000 live births at term in high-income countries, preterm babies born before 37 weeks have an HIE incidence of around 37.3/1000 babies born before 37 weeks of gestation, rising to an overall rate of HIE of 120/ 1000 in infants born before 28 weeks of gestation. [1,3] Survivors face lifelong neurodevelopmental problems, including learning and cognitive impairments, behavioral problems, cerebral palsy, and epilepsy. [4] The burden for individuals and their families and health and education economic costs are substantial. [4,5] To develop effective treatments or to appropriately utilize existing treatments requires that we fully understand how brain injury evolves and to identify biological markers (biomarkers) that allow us to determine phases of injury. Key to effective therapy is the knowledge that injury evolves in different phases over time-a latent phase of recovery of oxidative metabolism, which is followed by a secondary loss of cerebral energy metabolism during which time most brain cell injury occurs, followed by a tertiary phase of both repair and ongoing injury. [1,3,6] Therapeutic hypothermia (TH) is currently the only established treatment for HIE in babies born >36 weeks of gestation with moderate-severe HIE, and this treatment is now being cautiously explored for use in preterm babies. [1,2] The current clinical protocol for TH was based on our preclinical studies in term and preterm fetal sheep, which established that this therapy is only effective if started within 6 h after the end of an HI insult and continued for %3 days. [1-3] However, current clinical data show that many babies do not benefit from TH. [2] This in part reflects late recruitment of babies (typically 4-5 h) into treatment. However, it also reflects the fact that birth cannot always be taken as time zero. Many babies may also have experienced HI insults before birth, so that injury may have already evolved beyond the 6 h window of opportunity for TH efficacy.