Global climate change poses one of the greatest threats to biodiversity. Most analyses of the potential biological impacts have focused on changes in mean temperature, but changes in thermal variance will also impact organisms and populations. We assessed the combined effects of the mean and variance of temperature on thermal tolerances, organismal survival, and population growth in Drosophila melanogaster. Because the performance of ectotherms relates nonlinearly to temperature, we predicted that responses to thermal variation (±0° or ±5°C) would depend on the mean temperature (17° or 24°C). Consistent with our prediction, thermal variation enhanced the rate of population growth (r(max)) at a low mean temperature but depressed this rate at a high mean temperature. The interactive effect on fitness occurred despite the fact that flies improved their heat and cold tolerances through acclimation to thermal conditions. Flies exposed to a high mean and a high variance of temperature recovered from heat coma faster and survived heat exposure better than did flies that developed at other conditions. Relatively high survival following heat exposure was associated with low survival following cold exposure. Recovery from chill coma was affected primarily by the mean temperature; flies acclimated to a low mean temperature recovered much faster than did flies acclimated to a high mean temperature. To develop more realistic predictions about the biological impacts of climate change, one must consider the interactions between the mean environmental temperature and the variance of environmental temperature.