Sympathetic nervous activity (SNA) increases with exercise in normal subjects and this response is accentuated in heart failure (HF). The muscle metaboreceptor contribution to regulation of muscle SNA is blunted in HF whereas the mechanoreceptor contribution is augmented. The underlying causes of these changes in the muscle afferent function are poorly understood. This review is based on recently published data from our laboratory demonstrating that: 1) muscle interstitial ATP rises with twitch contraction and stimulates P2X receptors on thin fibers muscle afferents; 2) ATP accentuates muscle mechanoreceptor responses; 3) activation of VR1 receptor induces an increase in arterial blood pressure; and 4) cardiovascular responses to VR1 receptor stimulation are blunted and P2X mediated responses are augmented in rats with HF as compared with a control group of animals. These results suggest that alternations in VR1 and P2X receptors on muscle afferent nerves influence the processing of sensory information in HF and in turn may alter the magnitude and distribution of SNA during exercise in HF.