By 1950, comparative physiology was an established subfield whose broad agenda included (1) cataloging diversity, (2) using physiological information to reconstruct phylogenetic relationships, (3) elucidating how physiology mediates interactions between organisms and their environments, (4) identifying model systems for studying particular functions, and (5) using kind of organism as a pseudo‐experimental variable. Physiological ecology developed somewhat later, with an emphasis on the third goal. Both fields always had an evolutionary component, but only in the late 1970s did evolutionary physiology arise, borrowing rigorous inferential approaches from evolutionary biology and population/quantitative genetics. This newer subfield uses a range of approaches to ask whether the way organisms work influences the ways they evolve, and if so, how. Approaches include phylogenetically informed comparative studies, measurement of selection in wild populations, quantitative genetic analysis of trait heritabilities and correlations, and identification of genes involved in the adaptive process.Two primary foci of evolutionary physiology are the evolution of complex traits and the key role that organismal performance plays in mediating how natural and sexual selection act on individual variation within populations. Selection is often viewed as acting most directly on behavior (what an animal does in a given situation), which cannot exceed an animal's performance abilities (e.g., how fast it can sprint), which in turn depend on lower‐level morphological, physiological, and biochemical traits (e.g., muscle fiber type composition). If so, then behavior will often be at the leading edge of evolutionary (genetic) responses to selection. Moreover, given that animals usually have some excess capacity to perform relative to their typical daily activities, behavior may evolve to some extent without accompanying changes in exercise capacities. We have addressed this “behavior evolves first” hypothesis with experimental evolution.For >85 generations, we have bred 4 replicate lines of lab house mice for high voluntary wheel‐running behavior on days 5 and 6 of a 6‐day period of wheel access as young adults. The lines evolved rapidly, reaching selection limits after 17–27 generations, depending on line and sex. At these limits, mice from the High Runner lines ran ~3‐fold more than those from 4 non‐selected Control lines, due more to increased average running speed than the duration of daily running, but these two components show a trade‐off among the 4 HR lines. Studies aimed at uncovering the motivational/neurobiological basis of increased running have identified changes in specific brain regions (e.g., striatum), in multiple neural and endocrine signaling systems (e.g., dopamine, serotonin, endocannabinoids), and some evidence for exercise addiction. The evolution of high voluntary exercise has engendered various correlated responses, including reduced body size and body fat, increased maximal aerobic capacity and running endurance during forced treadmill exercise, larger joint surfaces, changes in inner ear morphology, reduced hindlimb muscle mass, alterations in circulating hormone concentrations, and increased adaptive plasticity in several traits.Support or Funding InformationU.S. N.S.F. DEB‐1655362This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.