Abstract Over the last 30 years there has been an increasing body of literature that has characterized the complex cascade of events that leads to neuronal and glial cell injury following perinatal hypoxia–ischaemia. Understanding the pathophysiology of hypoxic-ischaemic encephalopathy is important as this helps in delivering optimal targeted neuroprotective therapies. In this article we summarize the pathophysiological pathways that lead to the characteristic pattern of injury following a perinatal event in the term newborn infant.