Approximately 30 years ago, the myth that nervous system immaturity precluded neonates from pain perception and its negative effects was rejected. Neurobiologists further explored neurodevelopmental nociception. These observations strongly suggest that early pain experience contributes to neurodevelopmental outcome, pain thresholds, pain or stress-related behaviour and physiological responses in later life. Effective management of pain therefore remains an important indicator of the quality of care provided to neonates, not only from an ethical, but also from a short and long-term outcome perspective. Simultaneously, neonatal care itself has changed and data on neuro-apoptosis and impaired synaptogenesis following exposure to analgosedatives emerged. When developmental pharmacology concepts are applied to neonatal analgosedation, this means that this should be based on systematic assessment, followed by titrated administration of the most appropriate analgesic(s) with subsequent re-assessment to adapt treatment. This review will focus on the limitations of the available assessment tools, newly emerging analgosedatives in neonates to illustrate how these compounds can be integrated into the changing concepts of neonatal care.