 This review focuses on the long-term effects of repeated procedural pain-related stress in neonates born very pre-term, 24 to 32 weeks gestational age in relation to brain development, neurodevelopment, programming of stress systems, and later pain sensitivity. The study quantifies neonatal pain exposure as the number of invasive and or skin-breaking procedures during hospitalization in the NICU. The results suggest that early pain slash stress may influence the developing brain and thereby neurodevelopment and stress-sensitive behaviors, particularly in the most immature neonates. However, there is no evidence for greater prevalence of pain syndromes compared to children and adults born healthy at full-term. Non-pharmacological interventions to help parents reduce their infant stress may be brain-protective.