Robust evidence informs our understanding of the impacts of neonatal pain on brain growth and development and outcomes in childhood and adult life. However, evidence regarding optimal assessment and treatment in common clinical scenarios remains incomplete. In this setting, clinicians must synthesize available evidence regarding efficacy, and prioritize safety. Nonpharmacologic interventions should be systematic, safely implemented, and incorporate parents, when possible. Pharmacologic interventions should be protocolized for painful procedures, reflecting the magnitude and duration of the painful stimulus. Safe options for prolonged pain and agitation remain elusive and must be implemented with caution regarding both dose and duration.