This paper describes the potential impacts of warming temperatures and changing precipitation on plants, wildlife, invasive species, pests, and agricultural ecosystems across the multi-state region centered on Chicago, Illinois. We examine a geographic area that captures much of Lake Michigan, including a complex mosaic of urbanization and agriculture surrounding southern Lake Michigan. We consider species currently present within this broad region as well as species that are expected to move into or out of the area as climate zones shift northward through the coming century. Our analysis draws upon disparate data sources to compile projections. We conclude that a complex mixture of land use poses particular challenges to natural ecosystems in this region under climate change. Dispersal is likely to be limited for some species, and some populations of native taxa may already be reduced due to habitat loss. Other species can persist, even thrive, within a mixed landscape mosaic, provided natural areas and green spaces are available. If such spaces are somehow connected, they can provide opportunities for native species to inhabit and move through the metropolitan region (perhaps even better than the landscapes previously dominated by agriculture). Strategies for adapting regional agriculture and minimizing pest outbreaks also call for creative management intervention. With additional research, Chicago and its surrounding environs have an opportunity to provide leadership on effective management of natural resources under climate change.