In this talk I will discuss some of the multimodal and multiscale adaptations that animals (especially humans) make to stressors like exercise and hypoxia. I will also highlight that many insights come from 1) observational studies in a small number of animals or subjects, and 2) unusual patients that serve as human “knockouts” to test ideas about causality. A third point I will make is that physiology in specific and biomedical research in general needs to more fully leverage the August Krogh Principle as opposed to continuing to rely on narrowly focused and frequently inbred model systems. The goal of the talk is to be intentionally provocative.