The health-promoting benefits of exercise have been recognized for centuries, yet the molecular and cellular mechanisms for the acute and chronic adaptive response to a variety of physical activities remain incompletely described. This Perspective will take a forward view to highlight emerging questions and frontiers in the ever-changing landscape of exercise biology. The biology of exercise is complex, highly variable, and involves a myriad of adaptive responses in multiple organ systems. Given the multitude of changes that occur in each organ during exercise, future researchers will need to integrate tissue-specific responses with large-scale omics to resolve the integrated biology of exercise. The ultimate goal will be to understand how these system-wide, tissue-specific exercise-induced changes lead to measurable physiological outcomes at the whole-body level to improve health and well-being.