Urban areas are expected to continue their rapid growth in the twenty-first century. Globally, cities are major sources of greenhouse gases emissions and their high population densities make them potential focal points of vulnerability to global environmental change. Moreover, their reach, in terms of flows of materials and resources, extends far outside their borders. Evidently, it is no longer tenable to consider urban systems to be static artefacts constructed in a stable environment, nor continue to divorce them from the global context that influences many of the climatic and socio-economic changes within cities. Furthermore, the uncertainty in the future climatic and socio-economic conditions poses significant challenges for planners. A framework is proposed for analysing urban systems with evidence-based tools over extended time scales. This forms the basis of a manifesto for future challenges and research directions for this critical subject area, which ultimately will help engineers and urban planners to better understand the areas for which they are responsible and to develop adaptation strategies that can tackle the challenges posed by long-term global change and lead to more sustainable cities.