Increased awareness of pain in the newborn has led to the development of numerous assessment tools for use in neonatal intensive care units. Here, I argue that we still know too little about the neurophysiological basis for infant pain to interpret data from clinical observational measures. With increased understanding of how the neural activity and CNS connections that underlie pain behaviour and perception develop in the newborn will come better measurement and treatment of their pain. This review focuses upon two interconnected nociceptive circuits, the spinal cord dorsal horn and the somatosensory cortex in the brain, to highlight what we know and what we do not know about infant pain. The effectiveness of oral sucrose, widely used in clinical practice to relieve infant pain, is discussed as a specific example of what we do not know. This ‘hot topic review’ highlights the importance of new laboratory-based neurophysiological research for the treatment of newborn infant pain.