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In 2017, 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 fast track the oceans economy provides a challenge for ecosystem-based approaches to MSP. During the 2018 International Marine Conservation Congress, we convened a session to present particular challenges that will likely apply to any developing country seeking to increase profits from existing, or proposed, marine activities. Here we present six multi-disciplinary research projects that support ecosystem-based approaches to MSP in South Africa, by addressing the following knowledge gaps and specific key challenges: (1) the lack of data-derived measurements of ecosystem condition (and the need to validate commonly-used proxy measures); (2) the need to develop models to better understand the potential impacts of climate change on food webs and fisheries; (3) the slow implementation of an ecosystem approach to fisheries management, and the need to implement existing legal instruments that can support such an approach; (4) the paucity of evidence supporting dynamic ocean management strategies; (5) the requirement to manage conflicting objectives in growing marine tourism industries; and (6) the need to adopt systems thinking approaches to support integrated ocean management. We provide examples of specific research projects designed to address these challenges. The ultimate goal of this research is to advance a more integrated approach to ocean management in South Africa, using tools that can be applied in countries with similar socio-political and environmental contexts.