The Red Sea is one of the warmest and most saline seas on the planet. Yet, scleractinian corals have managed to flourish under these distinct conditions supporting one of the largest networks of coral reef ecosystems worldwide. Here, we summarize current knowledge on the ecophysiology of reef-building corals gained from 60 years of research in the Red Sea starting from insights in the 1960s to the most recent studies of the past few years. We provide a brief overview over seasonal dynamics and environmental gradients in the Red Sea that are used to study ecophysiological processes of corals under changing environmental and extreme conditions (i.e., temperature, salinity, nutrient, and light availability). We then focus on how this environmental variability shapes the central processes of coral physiology in the Red Sea covering the topics of photosynthesis, calcification, nutrient cycling, and reproduction. We continue by reporting the first physiological measurements of Red Sea deep-sea corals. Last, we discuss how, through the integration of traditional methods with recent developments in the omics field and model systems, we are now beginning to understand the complexity of processes that contribute to the ecological success of corals under these variable conditions. This synthesis may serve as a basis for future studies that aim to contribute to a better understanding of the impacts of environmental change on coral reefs in the Red Sea and the rest of the world.