The non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (paracetamol) are the most common analgesic drugs used in neonates and infants despite limited pharmacodynamic data. Both drugs act through inhibition of cyclooxygenase enzymes. Neonatal acetaminophen clearance is reduced in premature neonates (0.7 L h(-1) x 70 kg(-1)) and increases to 5 L h(-1) x 70 kg(-1) at term (40% adult rates); adult rates are reached within the first year of life; NSAID clearance follows similar trends. Volume of distribution is increased in the neonatal period. Dosing of both drug groups is tempered by concerns about toxicity. Acetaminophen hepatotoxicity is less common in neonates than in older children and adults, possibly due to reduced oxidative enzyme activity (e.g. CYP 2E1). Data concerning NSAID adverse effects in the neonatal period are few. Renal function is reduced 20% after NSAID use for patent ductus arteriosus closure in premature neonates and there is no increased frequency of intraventricular haemorrhage. No significant difference in the change in cerebral blood volume, change in cerebral blood flow, or tissue oxygenation index was found between administration of ibuprofen or placebo in neonates. Future studies should define concentration-response relationships for these drugs that are age and pathology specific.