Urbanization brings benefits and burdens to both humans and nature. Cities are key systems for integrated social-ecological research and the interdisciplinary journal of Ambio has published ground-breaking contributions in this field. This reflection piece identifies and discusses integration of the human and natural spheres in urban social-ecological research using the following foundational papers as important milestones: Folke et al. (1997), Ernstson et al. (2010) and Andersson et al. (2014). These papers each take unique approaches that aim to uncover core properties—processes, structures, and actors—of urban systems and set them into mutual relationship. This piece will end with a forward-looking vision for the coming 50 years of urban sustainability and resilience study in Ambio.