Mammalian skeletons experience peak locomotor stresses (force per area) that are 25 to 50% of their failure strength, indicating a safety factor of between two and four. The mechanism by which animals achieve a constant safety factor varies depending on the size of the animal. Over much of their size (0.1 to 300 kilograms), larger mammals maintain uniform skeletal stress primarily by having a more upright posture, which decreases mass-specific muscle force by increasing muscle mechanical advantage. At greater sizes, increased skeletal allometry and decreased locomotor performance likely maintain stresses constant. At smaller sizes, skeletal stiffness may be more critical than strength. The decrease in mass-specific muscle force in mammals weighing 0.1 to 300 kilogram indicates that peak muscle stresses are also constant and correlates with a decrease in mass-specific energy cost of locomotion. The consistent pattern of locomotor stresses developed in long bones at different speeds and gaits within a species may have important implications for how bones adaptively remodel to changes in stress.