Road safety in low-income countries (LICs) is a major concern, especially given the increasing levels of road crash injuries and fatalities across Africa and South Asia. A better understanding is needed, through research, of the underlying mechanisms of road safety in these developing contexts. There is, however, a need for a strategic approach to the research effort on Road Safety for LICs. The DfID-funded High Volume Transport (HVT) Applied Research Programme seeks to provide this approach, through connected and related research activities. The paper highlights salient issues from a comprehensive review of road safety in LICs and describes how it informs the current work and future outputs of the programme. Drawing on the review, HVT focuses on research gaps including (i) under-reporting of road crashes and weaknesses in road safety data systems; (ii) the interaction between road safety, vulnerable groups and disabilities; (iii) road crash social and economic cost estimates; (iv) social/behavioural aspects of driving cultures and behaviour that differ significantly from high income countries; and (v) capacity development of road safety institutions in LICs. The HVT programme has piloted innovative practice around road safety awareness of school communities, policy briefs and road safety guidelines for road sector institutions across Africa & South Asia. HVT will also support future research and capacity development activities on the challenge of building robust road safety data systems and addressing the gap in estimating the economic and social costs of road crashes at national levels across Africa and South Asia.