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The Master runner (age 35 y and above) represents a unique athletic patient. Lifelong participation in endurance running slows the inevitable age-related decline in aerobic function and muscular strength. Still, the Master runner does not escape the inevitable effects of aging. Master runners experience a steady decline in running performance, that is, typical and maximal running speeds, after the age of 50 years of age. Age-related declines in running performance are driven by a host of factors, including declining cardiovascular function, reduced muscular capacity, altered biomechanics, and greater susceptibility to running-related injury. This review discusses age-related changes in physiology, biomechanics, and running injury susceptibility and practical strategies to maximize running participation in the Master runner.