Extreme environments offer a unique look into the process of adaptation since the selection pressures experienced there are often singular and strong. I will tell two stories of vertebrate adaptation to extreme environments: adaptation of a small mammal to high altitude and of a migratory fish to varying salinity environments. Using the North American deer mouse as a model, I show that adaptation to high altitude occurs through selection on existing phenotypic plasticity in aerobic metabolic performance as well as shifts in hypoxia signaling pathways that underly responses to low oxygen. Using repeatedly derived freshwater populations of a marine herring (the alewife), I show that natural selection acts on the physiological and underlying gene regulatory processes of osmoregulation to facilitate adaptation to cool, freshwater all year long. By connecting genotype-to-phenotype across biological levels of organization, my work offers a uniquely “whole-organism” perspective on the mechanisms of adaptation.