There is substantial evidence to implicate a role of the carotid body (CB) chemoreflex in sympathetic and breathing dysregulation in several cardio-respiratory diseases, drawing renewed interest in its potential implications for clinical treatment and management. Evidence from both chronic heat failure (CHF) patients and animal models indicates that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in sympathetic nerve activity (SNA) and periodic breathing associated with the disease. Although this maladaptive change likely derives from altered function at all levels of the reflex arc, a change in afferent function of the CB is likely to be a main driving force. This review will focus on recent advances in our understanding of the physiological mechanisms that alter CB function in CHF and their potential translational impact on treatment of CHF.