Inadequate pain management in neonatal life impairs the neurodevelopmental outcome. It alters pain thresholds, pain and stress-related behavior, and physiologic responses in later life. At the same time, there are emerging animal experimental and human epidemiologic data on the impact of analgosedatives on neuroapoptosis and impaired neurodevelopmental outcome. As a consequence, the management of neonatal pain is in search of a new equilibrium since these conflicting (undertreatment versus overtreatment) observations are the main drivers of its current management. Such tailoring includes new treatment modalities, and also more effective implementation strategies. The search for tailored nonpharmacologic (ie, less invasive techniques, preventive strategies, complementary techniques) and pharmacologic (eg, dexmedetomidine, intravenous acetaminophen, remifentanil) treatment modalities are discussed and reflect the increased knowledge on neonatal pain management. Despite this increasing knowledge ("toolbox") regarding neonatal pain, there is still a major gap between knowledge ("what we know") and practice ("how we act"). Consequently, more research activity on methods for effective implementation of the available knowledge is needed. Illustrations of effective approaches, eg, the Evidence-Based Practice for Improving Quality (EPIQ) initiative, to bridge this gap are provided. This is followed by an intersubjective proposal on priorities for contemporary clinical management and a research agenda.