Adaptation of cropping systems to weather uncertainty and climate change is essential for resilient food production and long-term food security. Changes in climate result in substantial temporal modifications of cropping conditions, and rainfall and temperature patterns vary greatly with location. These challenges come at a time when global human population and demand for food are both increasing, and it appears to be difficult to find ways to satisfy growing needs with conventional systems of production. Agriculture in the future will need to feature greater biodiversity of crop species and appropriate design and management of cropping and integrated crop/animal systems. More diverse and longer-cycle crop rotations will need to combine sequences of annual row crops such as maize and soybean with close-drilled cereals, shallow-rooted with deep-rooted crops, summer crops with winter crops, and annuals with perennials in the same fields. Resilience to unpredictable weather will also depend on intercropping, with the creative arrangement of multiple interacting crop species to diversify the field and the landscape. Other multiple-cropping systems and strategies to integrate animals and crops will make more efficient use of natural resources and applied inputs; these include systems such as permaculture, agroforestry, and alley cropping. Future systems will be spatially diverse and adapted to specific fields, soil conditions, and unique agroecozones. Production resilience will be achieved by planting diverse combinations of species together in the same field, and economic resilience through producing a range of products that can be marketed through different channels. The creation of local food webs will be more appropriate in the future, as contrasted with the dominance of global food chains today. Materials considered “waste” from the food system, including human urine and feces, will become valuable resources to be cycled back into the natural environment and into food production. Due to the increasing scarcity of fertile land, the negative contributions of chemicals to environmental pollution, the costs of fossil fuels, and the potential for the economic and political disruption of supply chains, future systems will increasingly need to be local in character while still achieving adaptation to the most favorable conditions for each system and location. It is essential that biologically and economically resilient systems become productive and profitable, as well as environmentally sound and socially equitable, in order to contribute to stability of food production, security of the food supply, and food sovereignty, to the extent that this is possible. The food system cannot continue along the lines of “business as usual,” and its path will need to radically diverge from the recognized trends toward specialization and globalization of the early 21st century. The goal needs to shift from exploitation and short-term profits to conservation of resources, greater equity in distribution of benefits, and resilience in food supply, even with global climate change.