Climate change and land-cover change will have major impacts on biodiversity persistence worldwide. These two stressors are likely to interact, but how climate change will mediate the effects of land-cover change remains poorly understood. Here we use an empirically-derived model of the interaction between habitat loss and climate to predict the implications of this for biodiversity loss and conservation priorities at a global scale. Risk analysis was used to estimate the risk of biodiversity loss due to alternative future land-cover change scenarios and to quantify how climate change mediates this risk. We demonstrate that the interaction of climate change with land-cover change could increase the impact of land-cover change on birds and mammals by up to 43% and 24% respectively and alter the spatial distribution of threats. Additionally, we show that the ranking of global biodiversity hotspots by threat depends critically on the interaction between climate change and habitat loss. Our study suggests that the investment of conservation resources will likely change once the interaction between climate change and land-cover change is taken into account. We argue that global conservation efforts must take this into account if we are to develop cost-effective conservation policies and strategies under global change.