In most cases of neonatal hypoxic-ischemic encephalopathy, the exact timing of the hypoxic-ischemic event is unknown, and we have few reliable biomarkers to precisely identify the phase of injury or recovery in an individual patient. However, it is becoming increasingly clear that for neuroprotection in neonates to succeed, an understanding of the phase of injury is important to ascertain. In addition, in utero antecedents of chronic hypoxia, hypoxic preconditioning, intrauterine infection, and fetal gender may change the expected time course of injury. Neuroprotective interventions, such as hypothermia and N-acetylcysteine, currently have efficacy in human and animal studies only if instituted early in the inflammatory cascade. Although these cascades are currently being investigated, molecular mechanisms of recovery have received little attention and may ultimately reveal a window for therapeutic intervention that is much longer than current paradigms.