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The sustainable development of cities is increasingly recognized as crucial to meeting collectively agreed sustainability goals at local, regional and global scales, and more broadly to securing human well-being worldwide. The UN Sustainable Development Goals (SDGs) include a goal on cities (Goal 11), with most other goals and targets have urban applications and multi scalar implications for their implementation. Further, the interdependencies — including synergies and trade-offs —among the various SDGs are greater in cities, presenting both challenges and opportunities. A systems approach is urgently needed in urban research and policy analysis, but such an approach rarely features in current analysis or urban decision-making for various reasons. This paper explores four questions: why a systems approach is necessary, what defines such an approach, why has this rarely been adopted in practice, and what can be done to promote its use. We argue that a systems approach can reveal unrecognized opportunities to maximize co-benefits and synergies, guide management of inevitable trade-offs, and therefore inform prioritisation and successful solutions. We present four key issues for the effective implementation of the SDGs and the New Urban Agenda, which emerged from UN Habitat III Conference, namely: (a) a radical redesign of the multilateral institutional setup on urban issues; (b) promoting regenerative culture, behaviour, and design; (c) exploring ways to finance a systems approach; and (d) a new and enhanced role for science in sustainable development. The latter issue could be addressed through Future Earth’s Urban Knowledge-Action Network, which aims at co-designing and co-producing cutting-edge and actionable knowledge for sustainable cities bringing together researchers and urban decision-makers and practitioners.