The concept of One Health, which aims to drive improvements in human, animal and ecological health through an holistic approach, has been gaining increasing support and attention in recent years. While this concept has much appeal, there are few examples where it has been successfully put into practice. This Special Issue explores the challenges in African contexts, with papers looking at the complex interactions between ecosystems, diseases and poverty dynamics; at underlying social and political dimensions; at the potentials for integrative modelling; and at the changes in policy and practice required to realise a One Health approach. This introductory paper offers an overview of the 11 papers, coming from diverse disciplinary perspectives, that each explore how a One Health approach can work in a world of social, economic and environmental change.