Clinical and laboratory investigations of neonatal pain suggest that preterm neonates are more vulnerable to stress and painful procedures and have heightened responses to successive stimuli. Preterm infants receiving intensive care are subjected to frequent invasive and stressful procedures as well as more chronic environmental influences. Acute episodic pain may cause early neurologic injury. Repeated and prolonged exposure to pain may alter subsequent psychokinetic development, as well as affect long-term neurodevelopmental, behavioral and social-emotional outcome. Several pain measures exist to assess pain in full-term and preterm neonates, including behavioral indicators and physiological indicators of pain. Therapeutic interventions can provide comfort and analgesia in preterm neonates. Guidelines for preventing or treating neonatal pain and its adverse consequences include recognition of the sources of pain and routine assessments of neonatal pain, avoidance of recurrent painful stimuli and the use of specific non-pharmacological and pharmacological interventions.