There is convincing epidemiological evidence that regular physical activity, including structured exercise, is associated with improved health outcomes. This appears to be partly related to the total exercise energy expenditure. Over the years, many physiologists have examined the integrative biology of exercise to better understand physiological responses to homeostatic challenges. These insights have often been used to identify the physiological limits of, and the optimal strategies to enhance, athletic performance. Increasingly, studies in exercise biology provide new ideas on the mechanisms by which exercise exerts its beneficial effects on health. With increased application of emerging techniques in molecular and cell biology, there is now even greater understanding of the molecular mechanisms underpinning the adaptive responses to acute and chronic exercise. This information has the potential to optimise exercise interventions and to identify novel therapeutic strategies, including potential “exercise mimetics”, although whether full recapitulation of exercise effects can be achieved by one, or several, pharmacological agents is debated. Another prospect emerging from the ‘omics’ era is greater understanding of the physiological and molecular bases of individual variation in responses to exercise. Although the technology remains ahead of the biology, analysis of the large data sets being generated from exercise studies may one day result in precision “exercise medicine” and a really personalised trainer.