The long-term sustainability of wheat-based dryland cropping systems in the Inland Pacific Northwest (IPNW) of the United States depends on how these systems adapt to climate change. Climate models project warming with slight increases in winter precipitation but drier summers for the IPNW. These conditions combined with elevated atmospheric CO2, which promote crop growth and improve transpiration-use efficiency, may be beneficial for cropping systems in the IPNW and may provide regional opportunities for agricultural diversification and intensification. Crop modeling simulation under future climatic conditions showed increased wheat productivity for the IPNW for most of the century. Water use by winter wheat was projected to decrease significantly in higher and intermediate precipitation zones and increase slightly in drier locations, but with winter crops utilizing significantly more water overall than spring crops. Crop diversification with inclusion of winter crops other than wheat is a possibility depending on agronomic and economic considerations, while substitution of winter for spring crops appeared feasible only in high precipitation areas. Increased weed pressure, higher pest populations, expanded ranges of biotic stressors, and agronomic, plant breeding, economic, technology, and other factors will influence what production systems eventually prevail under future climatic conditions in the region.