Neonatal sepsis causes significant global morbidity and mortality, with the highest burden in resource-limited settings where 99% of neonatal deaths occur. There are multiple challenges to achieving successful treatment of neonates in this setting. Firstly, reliable and low-cost strategies for risk identification are urgently needed to facilitate treatment as early as possible. Improved laboratory capacity to allow identification of causative organisms would support antimicrobial stewardship. Antibiotic treatment is still hampered by availability, but also increasingly by antimicrobial resistance – making surveillance of organisms and judicious antibiotic use a priority. Finally, supportive care is key in the management of the neonate with sepsis and has been underrecognized as a priority in resource-limited settings. This includes fluid balance and nutritional support in the acute phase, and follow-up care in order to mitigate complications and optimise long-term outcomes. There is much more work to be done in identifying the holistic needs of neonates and their families to provide effective family-integrated interventions and complete the package of neonatal sepsis management in resource-limited settings.