Effective management of pain remains an important indicator of the quality of care provided to neonates. Since the review of McIntosh in this journal over a decade ago, an extensive number of papers on assessment, prevention, and treatment of pain have been reported. In addition, preclinical insights into neurodevelopmental aspects of pain processing and the neuro-apoptotic effects of analgesics and sedatives were unveiled. Based on the newly collected evidence, the practice of "one-drug, one dose and one treatment fits all" became obsolete, necessitating a more individualized analgesia, based on non-pharmacological and pharmacological therapies and preventive strategies for effective management of neonatal pain. The progress made is impressive, but the current major challenge is to implement the available knowledge in clinical care. Future research should therefore focus on the evaluation of the effectiveness of non-opioid and moderately potent opioids compared to morphine and should also describe the methods to facilitate effective implementation. Finally, there is an extensive field of procedural techniques that need to be evaluated on their pain related response.