As outlined in Figure 1, it is likely that a series of interventions beginning in the field and continuing through the emergency department, ICU, rehabilitation center, and possibly beyond, will be needed to optimize clinical outcome after severe TBI or asphyxial CA in infants and children. Despite the many differences between these two important pediatric insults, it is likely that many of the therapies targeting neuronal death, in either condition, will need to be administered early after the insult, possibly at the injury scene. Even cerebral swelling, a pathophysiologic derangement routinely treated in the PICU, almost certainly is better prevented rather than treated. Finally, this review includes, for one of the first times, a brief discussion of additional horizons in the management of patients with severe brain injury, namely, manipulation of the injured circuitry and stimulation of regeneration. Further research is needed to define better the pathobiology of these two important conditions at the bedside, to understand the optimal application of contemporary therapies, and to develop and apply novel therapies. The tools necessary to carry out these studies are materializing, although the obstacles are great. This difficult but important challenge awaits further investigation by clinician-scientists in pediatric neurointensive care.