Despite the improved survival of tiny preterm neonates, their neurodevelopmental outcomes remain a cause for grave concern. The authors propose two primary mechanisms leading to enhanced neuronal cell death in the immature brain: (1) NMDA-mediated excitotoxicity resulting from repetitive or prolonged pain, and (2) enhanced naturally occurring neuronal apoptosis during early development due to multiple metabolic stresses or lack of social stimulation. The pattern and magnitude of abnormalities will depend on genetic variability as well as the timing, intensity, and duration of adverse environmental experiences. Thus, cumulative brain damage during infancy will finally lead to reductions in brain volume, abnormal behavioral and neuroendocrine regulation, and poor cognitive outcomes during childhood and adolescence. The public health and economic importance of preventing or ameliorating the subtle brain damage caused by these mechanisms cannot be overestimated. This certainly justifies concerted efforts by neuroscientists and clinicians to investigate the mechanisms underlying early neuronal injury, to minimize the impact of adverse experiences and environmental factors in neonates, and to develop novel therapeutic strategies for improving the cognitive and behavioral outcomes of ex-preterm neonates.