The arterial vessels within the arms and legs are exposed to different hydrostatic pressures and blood-flow demands during the course of daily life. There is compelling indirect evidence that arterial reactivity differs in the arms and legs of humans; greater blood-flow responses to physiological vasodilator stimuli are generally reported in the arms of healthy younger subjects, whereas greater sympathetically mediated vasoconstrictor responsiveness is generally observed in the legs. Limb blood-flow responses to local arterial infusions of vasoactive agents reveal a similar pattern of heterogeneity in human arms versus legs. The advantages and assumptions of these pharmacological approaches for evaluating limb arterial reactivity are discussed, and methodological issues pertaining to the normalization and interpretation of vascular responses in the human arm and leg are critically examined. The article concludes with recent data from our laboratory indicating that limb-specific variation in arterial function may be age-, sex-, and physical activity dependent.