Although considerable epidemiologic and clinical evidence suggests that structured exercise, increased lifestyle activity, or both are cardioprotective, the absolute and relative risk of cardiovascular and musculoskeletal complications appear to increase transiently during vigorous physical activity. The estimated relative risk of exercise-related cardiac events ranges from 2.1 to 56 and is highest among habitually sedentary individuals with underlying cardiovascular disease who were performing unaccustomed vigorous physical exertion. Moreover, an estimated 7 million Americans receive medical attention for sports and recreation-related injuries each year. These risks, and their modulators, should be considered when endorsing strenuous leisure time or exercise interventions. If the current mantra "exercise is medicine" is embraced, underdosing and overdosing are possible. Thus, exercise may have a typical dose-response curve with a plateau in benefit or even adverse effects, in some individuals, at more extreme levels.