Recent advances in the clinical management of at-risk pregnancy and care of the newborn have reduced morbidity and mortality among sick neonates, and improved our knowledge of factors that influence the risks of brain injury. In parallel, the refinement of imaging techniques has added to the ability of clinicians to define the etiology, timing and location of pathologic changes with diagnostic and prognostic relevance to the developing fetus and newborn infant. Abnormalities of brain growth, or injury to the developing brain can occur during pregnancy; during labor and delivery, hypoxia, acidosis and ischemia pose major risks to the fetus. Defined practices for the management of pregnancy and delivery, and evidence-based strategies for care in the newborn period are influencing outcome. However, newborn infants, especially those born prematurely, remain at risk from situations that can cause or worsen brain injury. The literature reviewed here explains the mechanisms and timing of injury, and the importance of hypoxia, ischemia, hypotension and infection; describes current diagnostic strategies, neuroimaging technologies and care entities available; and outlines approaches that can be used to prevent or mitigate brain injury. Some show particular promise, and all are relevant to lowering the incidence and severity of brain damage.