Optimal analgesia remains a major challenge for all involved in the care of (critically) ill newborns. The rapid changes in liver metabolism involving maturation of liver enzymes and renal clearance of drugs render (extreme) very low birth weight infants different from newborns of later postconceptional age with regards to the use of opioids such as morphine and fentanyl. Acute and/or procedural pain has been investigated fairly recently in randomized controlled trials and there are now guidelines. The long-term effects of opioid use in this particular age group of vulnerable babies await further evaluation.