Clinical and laboratory investigations of neonatal pain suggest that preterm neonates have an increased sensitivity to pain and that acute painful stimuli lead to the development of prolonged periods of hyperalgesia. Non-noxious stimuli during these periods of hyperalgesia may expose preterm neonates to established or chronic pain. Acute physiologic changes caused by painful or stressful stimuli can be implicated as important factors in the causation or subsequent extension of early intraventricular hemorrhage (IVH) or the ischemic changes leading to periventricular leukomalacia (PVL). Therapeutic interventions that provide comfort/analgesia in preterm neonates were correlated with a decreased incidence of severe IVH. Long-term follow-up studies of preterm neonates may substantiate the preliminary data associating repetitive painful experiences with some of the neurobehavioral and developmental sequelae resulting from neonatal intensive care.