Inadequate pain management in neonatal life impairs short-term outcomes, as well as long-term neurodevelopmental outcomes because it alters pain thresholds, pain- or stress-related behavior, and physiological responses. However, there are also emerging animal and human epidemiological data showing the impact of the use of analgo sedatives on neuro-apoptosis and impaired neurodevelopmental outcomes. Consequently, neonatal pain management is in search of a new balance, and these conflicting observations are the main drivers to tailor pain management in neonates. Adequate pain management is based on prevention, assessment, and treatment with subsequent reassessment. Issues related to prevention and assessment tools are covered. Non-pharmacological (e.g., complementary interventions like facilitated tucking, nonnutritive sucking) and pharmacological (e.g., acetaminophen, opioids, ketamine, propofol) treatment modalities have been reviewed and reflect the increased knowledge on neonatal pain management. Each topic ends with take-home messages that in part reflect our personal opinion on the current status of this topic.