Even without climate change the current trajectory in yields of the major food crops is not sufficient to meet demand from population and income growth without an enormous expansion of cropped area. Such an expansion would come at the expense of the remaining rainforest, wetlands, and grassland savannahs. Conversion of these C-rich ecosystems would hasten the rise in greenhouse gas (GHG) emissions and greatly reduce habitat for biodiversity. To avoid this conversion will require a rapid acceleration in the rate of gain in crop yields on existing farmland, and these higher yields must be achieved while also reducing GHG emissions from crop production and preserving soil and water quality. The process of increasing yields while reducing the environmental footprint of crop production is called “ecological intensification.” Achieving ecological intensification in all of the world's most productive cropping systems represents the single greatest scientific challenge facing humankind. Climate change adds another dimension to this challenge because there remains substantial uncertainty about the impact of increasing temperatures and [CO2] on crop yields and rainfall distribution. Ultimately, global food production capacity is determined by crop yield potential, the amount of arable land suitable to support crop production, and water supply. Lack of agreement between estimates of yield response to increased temperature derived from simulation models versus estimates obtained from the relationship between growing season temperature and crop yields is cause for concern. Either models are not capturing the full impact of temperature, or the empirical relationships are confounded by other factors. In either case, there is an urgent need to better understand the fundamental basis of crop yield potential and the impact of climate change on it. The key research questions embodied in this challenge will be discussed, as will the role of biotechnology.