In 2016, South Africa became the first African country to draft Marine Spatial Planning (MSP) legislation. The underlying legal framework supports the achievement of ecological, social and economic objectives, but a national policy to grow the oceans economy provides a challenge for ecosystem-based approaches to MSP. During the 2018 International Marine Conservation Congress in Borneo, we convened a special session to discuss particular challenges that will likely apply to any developing country seeking to increase profits from existing, or proposed, marine activities. Here we present six inter-disciplinary research projects that support ecosystem-based approaches to MSP in South Africa, by addressing the following key challenges: (1) measuring ecosystem condition; (2) modelling impacts of climate change on food webs and fisheries; (3) managing fisheries with an ecosystem approach; (4) using dynamic ocean management to resolve conflicts between fisheries and threatened species; (5) managing conflicting objectives in a growing marine tourism industry; and (6) developing scenarios for alternative management strategies in complex marine social-ecological systems.