With rapid global urbanization, the importance of understanding relationships between the changing urban environment and human health and wellbeing is being increasingly recognized. However, the science underlying the complexity of linkages is poorly developed. In this paper, we explore the different types of health and wellbeing risks in the urban environment, their dynamic, ever evolving nature, and define both their spatial and socioeconomic dimensions. We also present the new innovative program on Health and Wellbeing in the Changing Urban Environment that was launched recently by the International Council for Science (ICSU) wherein an integrated systems approach is recommended to address this complexity. We conclude by identifying key elements needed for the success of the new science initiative.