Brain injury is the leading cause of death in pediatric ICU. Current evidence supports the use of therapeutic hypothermia (TH) in unconscious patients after out-of-hospital cardiac arrest when the initial heart rhythm was ventricular fibrillation. TH has been proved to be also beneficial in term neonates after hypoxic-ischemic encephalopathy (HIE) and in children with traumatic brain injury (TBI). Recent reports have also investigated TH for the treatment of superrefractory status epilepticus. The clinical application of TH is based on the possibility to inhibit or lessen a myriad of destructive processes (including excitotoxicty, neuroinflammation, apoptosis, free radical production, seizure activity, blood- brain barrier disruption, blood vessel leakage) that take place in the injured tissue following ischemia-reperfusion. TH may also represent a useful tool when conventional therapy fails to achieve an effective control of elevated intracranial pressure. This review is aimed to provide an update of the available literature concerning this intriguing topic.