Perinatal hypoxic-ischaemic injury (HII) is a significant cause of neurodevelopmental impairment and disability. Studies employing 31P magnetic resonance spectroscopy to measure phosphorus metabolites in situ in the brains of newborn infants and animals have demonstrated that transient hypoxia-ischaemia leads to a delayed disruption in cerebral energy metabolism, the magnitude of which correlates with the subsequent neurodevelopmental impairment. Prominent among the biochemical features of HII is the loss of cellular ATP, resulting in increased intracellular Na+ and Ca2+, and decreased intracellular K+. These ionic imbalances, together with a breakdown in cellular defence systems following HII, can contribute to oxidative stress with a net increase in reactive oxygen species. Subsequent damage to lipids, proteins, and DNA and inactivation of key cellular enzymes leads ultimately to cell death. Although the precise mechanisms of neuronal loss are unclear, it is now clear both apoptosis and necrosis are the significant components of cell death following HII. A number of different factors influence whether a cell will undergo apoptosis or necrosis, including the stage of development, cell type, severity of mitochondrial injury and the availability of ATP for apoptotic execution. This review will focus on some pathological mechanisms of cell death in which there is a disruption to oxidative metabolism. The first sections will discuss the process of damage to oxidative metabolism, covering the data collected both from human infants and from animal models. Following sections will deal with the molecular mechanisms that may underlie cerebral energy failure and cell death in this form of brain injury, with a particular emphasis on the role of apoptosis and mitochondria.