The anatomic and physiological bases for nociception are present even in very preterm neonates. Neonates show the same behavioral, endocrine, and metabolic responses to noxious stimuli as older subjects. Preterm infants appear to be more sensitive to painful stimuli and have heightened responses to successive stimuli. Infants receiving intensive care are subjected to frequent stressful procedures and also chronic noxious influences related to the environment of care. Inflammatory conditions such as necrotizing enterocolitis may also cause pain. Untreated pain in babies is associated with increased major morbidity and mortality. Nonpharmacological interventions, including environmental modification and comforting during procedures reduce stress. Intravenous opiates are the mainstay of pharmacological analgesia. A pure sedative agent can provide physiological stability in settings in which there are less acutely painful stimuli or when there are adverse effects from, or tolerance to, opiates. Local anesthesia of skin and mucous membranes is helpful for invasive procedures. Antipyretic analgesics such as acetaminophen have a role in inflammatory pain.