Global climate change in the form of rising temperatures and increasingly variable rainfall patterns, along with heightened competition for scarce natural resources, potentially threatens the sustainability of cotton cropping systems. Thus, future cotton production is likely to occur under an increased prevalence of multiple abiotic stresses, including extreme and prolonged high temperatures and water deficits. Therefore, it is of increasing relevance that the combined effects of heat and drought stresses on cotton productivity are more comprehensively examined under field conditions. This article reviews the separate influences of heat and drought stress on cotton, outlines known effects of the combination of high temperature and water deficit on cotton and model plant species, discusses the genetic dissection of heat or drought stress tolerance traits in cotton, investigates the potential of field-based phenotyping methods for evaluating the response of cotton plants to heat and drought stresses, and, finally, offers perspectives on the development of stress-resilient cotton germplasm. Importantly, the integration of approaches from several disciplines is needed to allow cotton breeders to efficiently develop superior cultivars for optimal stress resilience in a farmer’s field.