: Neonatal brain hypoxic-ischemic injury represents a serious health care and socio-economical problem since it is one of the most common causes of mortality and morbidity of newborns. Neonatal hypoxic-ischemic encephalopathy is often associated with signs of perinatal asphyxia, with an incidence of about 2-4 per 1,000 live births and mortality rate up to 20%. In about one half of survivors, cerebral hypoxic-ischemic insult may result in more or less pronounced neuro-psychological sequelae of immediate or delayed nature, such as seizures, cerebral palsy or behavioural and learning disabilities, including attention-deficit hyperactivity disorder. Hypoxic-ischemic injury develops as a consequence of transient or permanent restriction of blood supply to the brain. Severity of hypoxic-ischemic encephalopathy varies depending on the intensity and duration of hypoxia-ischemia, on the type and size of the brain region affected, and on the maturity of the foetal/neonatal brain. Though a primary cause of hypoxic-ischemic injury is lack of oxygen in the neonatal brain, underlying mechanisms of subsequent events that are critical for developing hypoxic-ischemic encephalopathy are less understood. Their understanding is however necessary for elaborating effective management for newborns that underwent cerebral hypoxic-ischemic insult and thus are at risk of a negative outcome. The present paper summarizes current knowledge on cerebral hypoxic-ischemic injury of the neonate, fundamental processes involved in etiopathogenesis, with a special focus on cellular and molecular mechanisms and particular attention on certain controversial aspects of oxidative stress involvement.