One of the enduring lessons of cities is the essential relationship between grey infrastructure (e.g., streets and buildings) and green infrastructure (e.g., parks and open spaces). The design and management of natural resources to enhance human health and well-being may be traced back thousands of years to the earliest urban civilizations. From the irrigation projects of the Indus Valley and the aqueducts of the Roman Empire to integrated systems of landscaped urban parks and street trees in contemporary times, humans have sought to harness the capacity of nature to advance city life. This article presents a systems science framework that delineates critical relationships between grey and green elements of cities and human health and well-being by modeling the complex, dynamic problem of asthma in socioeconomically disadvantaged city neighborhoods. By understanding the underlying structure of urban spaces and the importance of social interactions, urban planners, public health officials, and community members may capitalize on opportunities to leverage resources to improve the health and well-being of urban populations and promote social justice and health equity.