ABSTRACT: Unlike quadrupeds, human limbs are exposed to differing homeostatic challenges and uses, which results in significant functional heterogeneity between the arms and legs. In these ACSM symposium proceedings, we report findings from three studies with the overall aim of investigating between-limb vascular differences through evaluation of arm (brachial artery) and leg (common, superficial, and deep femoral arteries) limb blood flow (ultrasound Doppler) during isolated-limb-specific exercise and after postcuff occlusion hyperemia. In a study of young, trained cyclists, a substantial conduit vessel vasodilation (deep femoral artery, ~9%) was observed during exercise, but responsiveness normalized to shear stimuli was still less than a conduit vessel in the arm. A subsequent aging study did not demonstrate any significant difference in resting leg or arm blood flow between young and old subjects when flow was normalized for muscle mass. However, we observed an approximately 10-15% reduction in exercising leg blood flow and vascular conductance in these older subjects, whereas exercising arm blood flow was similar between age groups. A separate aging study evaluated age-related changes in flow-mediated vasodilation (FMD), with the older group enrolled in a 6-wk knee-extensor exercise training program. Before training, a significant FMD was observed in the arm of young (3 ± 1%) but not old (1 ± 1%) subjects, and a significant leg FMD was observed in both groups. However, pretraining arm vasodilation was similar between young and old when normalized for shear rate. Exercise training significantly improved arm FMD (5 ± 1%), whereas leg FMD was unchanged. Collectively, these studies demonstrate a significant between-limb vascular heterogeneity in humans that is influenced by age and by exercise training.