This work reports on the main physical processes that arise in the environment of the megacity from the “urban metabolism”—the complex interactions of the climate with the activities performed in the city and its built structure and texture—as well as on associated large-scale processes that generate hazards for the megacity’s inhabitants. It is estimated that in a few decades most of the world’s population will live in urban centers. Both the growth of megacities and climate change will increase the vulnerability of huge sectors of the population to climatic consequences of the urban metabolism. These include urban heat islands, pollution, and extreme weather events such as heat waves and floods. Developing policies to mitigate these threats will require integrating scientific knowledge with management skills, communication among cities about effective approaches, and taking into account residents’ needs for health and the capacity to live safely.