Reducing neonatal mortality remains a challenge with an estimated 3.0 million neonatal deaths in 2011, three-quarters of these in sub-Saharan Africa and Southern Asia. The leading causes of neonatal death globally are complications of preterm birth, intrapartum-related causes and infections. While post-neonatal, under-5 deaths fell by 47% between 1990 and 2011, neonatal deaths only fell by 32% and they now account for 43% of all under-5 child deaths. This article reviews the progress in reducing neonatal deaths in high-burden countries and presents an overview of known effective interventions to reduce neonatal mortality and the challenges faced in implementing these in high-burden settings. Effective action is possible to reduce neonatal mortality, but innovative approaches to implementation will be required if these preventable deaths are to be avoided.