Hot temperatures in combination with high humidity cause human discomfort and may increase morbidity and mortality. A global climate model with an embedded urban model is used to explore the urban-rural contrast in the wet-bulb globe temperature, a heat stress index accounting for temperature and humidity. Wet-bulb globe temperatures are calculated at each model time step to resolve the heat stress diurnal cycle. The model simulates substantially higher heat stress in urban areas compared to neighbouring rural areas. Urban humidity deficit only weakly offsets the enhanced heat stress due to the large night-time urban heat island. The urban-rural contrast in heat stress is most pronounced at night and over mid-latitudes and subtropics. During heatwaves, the urban heat stress amplification is particularly pronounced. Heat stress strongly increases with doubled CO2 concentrations over both urban and rural surfaces. The tropics experience the greatest increase in number of high-heat-stress nights, despite a relatively weak similar to 2 degrees C warming. Given the lack of a distinct annual cycle and high relative humidity, the modest tropical warming leads to exceedance of the present-day record levels during more than half of the year in tropical regions, where adaptive capacity is often low. While the absolute urban and rural heat stress response to 2 x CO2 is similar, the occurrence of nights with extremely high heat stress increases more in cities than surrounding rural areas. Citation: Fischer, E. M., K. W. Oleson, and D. M. Lawrence (2012), Contrasting urban and rural heat stress responses to climate change, Geophys. Res. Lett., 39, L03705, doi: 10.1029/2011GL050576.