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.