This paper describes a global research programme on the complex systemic connections between urban development and health. Through transdisciplinary methods the Complex Urban Systems for Sustainability and Health (CUSSH) project will develop critical evidence on how to achieve the far-reaching transformation of cities needed to address vital environmental imperatives for planetary health in the 21st Century. CUSSH’s core components include: (i) a review of evidence on the effects of climate actions (both mitigation and adaptation) and factors influencing their implementation in urban settings; (ii) the development and application of methods for tracking the progress of cities towards sustainability and health goals; (iii) the development and application of models to assess the impact on population health, health inequalities, socio-economic development and environmental parameters of urban development strategies, in order to support policy decisions; (iv) iterative in-depth engagements with stakeholders in partner cities in low-, middle- and high-income settings, using systems-based participatory methods, to test and support the implementation of the transformative changes needed to meet local and global health and sustainability objectives; (v) a programme of public engagement and capacity building. Through these steps, the programme will provide transferable evidence on how to accelerate actions essential to achieving population-level health and global climate goals through, amongst others, changing cities’ energy provision, transport infrastructure, green infrastructure, air quality, waste management and housing.