Complexities and uncertainties surrounding urbanization and climate change complicate water resource sustainability. Although research has examined various aspects of complex water systems, including uncertainties, relatively few attempts have been made to synthesize research findings in particular contexts. We fill this gap by examining the complexities, uncertainties, and decision processes for water sustainability and urban adaptation to climate change in the case study region of Phoenix, Arizona. In doing so, we integrate over a decade of research conducted by Arizona State University’s Decision Center for a Desert City (DCDC). DCDC is a boundary organization that conducts research in collaboration with policy makers, with the goal of informing decision-making under uncertainty. Our results highlight: the counterintuitive, non-linear, and competing relationships in human–environment dynamics; the myriad uncertainties in climatic, scientific, political, and other domains of knowledge and practice; and, the social learning that has occurred across science and policy spheres. Finally, we reflect on how our interdisciplinary research and boundary organization has evolved over time to enhance adaptive and sustainable governance in the face of complex system dynamics.