This chapter provides an overview of the epidemiology and adverse outcomes associated with untreated pain in neonates, in addition to current best evidence regarding the assessment, prevention and management of neonatal pain. Most guidelines on neonatal pain management declare pain assessment to be essential for achieving optimal pain and stress management. Investigations into the efficacy of using machine learning automated techniques to accurately analyse signals from infants and evaluate if they indicate pain are ongoing. Facilitated tucking is a physical containment intervention that involves placing hands on the head and limbs of an infant undergoing a painful procedure to maintain them in a side-lying flexed fetal position. Paracetamol is one of the most commonly used analgesic drugs in the neonatal intensive care unit. Opioids are the mainstay for the effective treatment of moderate to severe pain across all age groups, including neonates.