Neonatal intensive care exposes preterm neonates to a series of repeated, randomly occurring invasive procedures and handling, resulting in acute pain, chronic pain, and prolonged stress during a critical window associated with epochal brain development. Characteristics of the immature pain system in preterm neonates (such as a low pain threshold, prolonged periods of windup, overlapping receptive fields, immature descending inhibition) predisposes them to greater clinical and behavioral sequelae from inadequately treated pain than older age groups. Evidence for developmental plasticity in the neonatal brain suggests that repetitive painful experiences during this period or prolonged exposure to analgesic drugs may alter neuronal and synaptic organization permanently. Traditionally, clinicians have chosen the perspective that routine use of analgesic or sedative drugs in preterm neonates may create more problems than minimal therapy. However, the immediate and long-term consequences of inadequately treated pain have forced them to reconsider the risk-benefit ratios for such therapy. Whereas the short-term consequences of prolonged analgesic therapy in human neonates are well-known (tolerance, withdrawal, ventilator dependency), long-term consequences are relatively unknown. Advances in the study of repetitive pain associated with routine NICU care have challenged the perspective that prolonged pain and stress were inevitable consequences of premature birth.