Under field conditions crops are routinely subjected to a number of different abiotic stress factors simultaneously. Recent studies revealed that the response of plants to a combination of different abiotic stresses is unique and cannot be directly extrapolated from simply studying each of the different stresses applied individually. These studies have also identified specific regulatory transcripts, combinations of metabolites and proteins, and physiological responses that are unique to specific stress combinations, highlighting the importance of studying abiotic stress combination in plants. Here we describe the interactions between drought and other abiotic stresses with emphasis on drought and heat stress. We compile new data about the different molecular, physiological and metabolic adaptations of different plants and crops to this stress combination and we highlight the importance of reactive oxygen species (ROS) metabolism and stomatal responses for plant acclimation to drought and heat stress combination. We further emphasize the need for developing crops with enhanced tolerance to drought and heat stress combination in order to mitigate the negative impacts of predicted global climatic changes on agricultural production worldwide.