ABSTRACT: Unlike quadrupeds, human limbs are exposed to differing homeostatic challenges and uses. The arms are not exposed to a large hydrostatic pressure and contain a relatively small muscle mass that is not typically engaged in heavy work. In contrast, the legs have a large blood volume, experience significant hydrostatic pressures, and contain the majority of the body's muscle mass, which is used regularly to perform the significant work of locomotion. This raises the question of whether skeletal muscle blood flow and metabolism differ between limbs and whether these responses may be altered during exercise as a consequence of aging and disease. Initially, we examine the long standing question of how the body copes with the involvement of both sets of limbs and the large muscle mass that this entails, restrained by a finite cardiac output and a need to defend arterial blood pressure. We therefore evaluate the similarities and differences in exercising muscle blood-flow control in the upper and lower limbs, with respect to exercise onset kinetics, intrinsic vasoreactivity of the resistance vessels at rest and during exercise, and the role of gender and the aging process in limb-specific responses. It is concluded that blood flow and pressure when multiple limbs are simultaneously recruited is facilitated by sympathetically mediated vasoconstriction. Inherent limb differences, in terms of skeletal muscle metabolism and blood flow, do exist, and elucidating the mechanisms underlying limb-specific adaptations will be important for interpreting abnormal vascular function attributable to healthy aging and disease.