The cardiovascular and hemodynamic adjustments to exercise are primarily mediated by alterations in parasympathetic and sympathetic neural activity. These changes in autonomic neural outflow are mediated via three distinct neural control mechanisms: central command, exercise pressor reflex (EPR) and the arterial baroreflex. Central command is a feedforward mechanism that, through signals originating in higher brain centers, activates cardiovascular and somatomotor systems in parallel. The EPR is a feedback peripheral neural drive originating in skeletal muscle. The arterial baroreflex provides further modulation via tonically active baroreceptors, located in the carotid and aortic arteries. As such, the alterations in autonomic outflow during physical activity are carefully controlled by these neural inputs to induce changes in heart rate, stroke volume and total peripheral resistance and evoke increases in arterial blood pressure (BP) appropriate for the metabolic demands of the exercising muscle. Although all three neural mechanisms are important for cardiovascular regulation during exercise, considerable attention has been given to the EPR due to its importance determining the magnitude of sympathoexcitation during exercise. The sensory component of the EPR is comprised of group III and IV skeletal muscle afferents that respond to both mechanical (i.e., muscle mechanoreflex) and metabolic (i.e., muscle metaboreflex) stimuli. It should be noted, however, that both type III and IV afferents show a degree of polymodality and may readily respond to either mechanical or metabolic provocation. The muscle mechanoreflex can be activated by mechanical stretch in humans, however its effects on cardiovascular responses appear small and transient. As a result, the evoked hemodynamic consequences to passive stretch of leg or arm muscles are limited in humans. In contrast, the muscle metaboreceptors are paramount in generating the reflex increases in sympathetic outflow during isometric exercise in normal physiological states. In humans, muscle metaboreflex activation can be isolated by means of circulatory arrest of the active limb just before the cessation of exercise. During this maneuver, metabolic by-products of muscle contraction are trapped in skeletal muscles and stimulate metabolically sensitive afferents fibers. Stimulation of these afferents results in an elevated blood pressure achieved in part by sympathetically-mediated increases in systemic vasoconstriction, with elevations in heart rate playing a minor role. Importantly, this maneuver isolates the muscle metaboreflex from central command and muscle mechanoreflex. Overall, while it is well established that the EPR is one of the principal mediators of the cardiovascular response to exercise, the receptors activating the group III and IV fibers that are important to EPR function remains unclear. Recent animal studies have reported that either capsaicin balm or infusion of capsazepine attenuates the pressor response to muscle contraction, indicating the transient receptor potential vanilloid1 (TRPv1) receptor (localized on the group IV afferent neuron) as an important mediator of the EPR via its metabolic component (named muscle metaboreflex). Whether these findings can be extended to human remains to be determined. Based on humans studies performed in our laboratory, I will provide evidence that capsaicin-based analgesic balm effectively attenuates BP (photoplethysmography), sympathetic outflow (peroneal microneurgraphy) and vasconstrictory (Doppler Ultrasound) responses evoked by metabolically sensitive skeletal muscle afferents in humans. These data are consistent with the concept that TRPv1 receptors contribute to the EPR in humans, via its metabolic component.