Reef-building corals provide the foundation for the structural and biological diversity of coral-reef ecosystems. These massive biological structures, which can be seen from space, are the culmination of complex interactions between the tiny polyps of the coral animal in concert with its unicellular symbiotic algae and a wide diversity of closely associated microorganisms (bacteria, archaea, fungi, and viruses). While reef-building corals have persisted in various forms for over 200 million years, human-induced conditions threaten their function and persistence. The scope for loss associated with the destruction of coral reef systems is economically, biologically, physically and culturally immense. Here, we provide a micro-to-macro perspective on the biology of scleractinian corals and discuss how cellular processes of the host and symbionts potentially affect the response of these reef builders to the wide variety of both natural and anthropogenic stressors encountered by corals in the Anthropocene. We argue that the internal physicochemical settings matter to both the performance of the host and microbiome, as bio-physical feedbacks may enhance stress tolerance through environmentally mediated host priming and effects on microbiome ecological and evolutionary dynamics.