We examine potential regional-scale impacts of global climate change on sustainability of irrigated agriculture, focusing on the western San Joaquin Valley in California. We consider potential changes in irrigation water demand and supply, and quantify impacts on cropping patterns, groundwater pumping, groundwater levels, soil salinity, and crop yields. Our analysis is based on archived output from General Circulation Model (GCM) climate projections through 2100, which are downscaled here to the scale of the study area (~30 km across). We account for uncertainty in GCM climate projections by considering output from two different GCM’s, each using three greenhouse gas emission scenarios. Significant uncertainty in projected precipitation translates into uncertainty of future water supply, ranging from an increase of 10% to a decrease of 30% in 2100. On the other hand, temperature projections are much less variable, resulting in consistent projections of crop water demand for all climate change scenarios. Crop water demand is expected to change very little, due to compensating effects of rising temperature on evaporative demand and crop growth rate. Reductions in surface water supply are projected to be offset by groundwater pumping and land fallowing. Simulations of subsurface flow and salt transport with a regional-scale hydro-salinity model suggest a small expansion in salt-affected area, compared to current conditions. However, in all scenarios salinity is expected to increase in downslope areas, thereby limiting crop production. This is especially significant given an anticipated demand-driven switch to high-value, salt-sensitive crops. Results show that technological adaptation, such as improvements in irrigation efficiency, may partly mitigate these effects.