Given the importance of adrenergic neural functioning in cardiovascular control, the hypothesis that an elevation in sympathetic drive represents a key pathophysiological feature of diseases characterized by an impairment in cardiac or renal function has been long considered. However, modern approaches to directly quantify sympathetic nerve firing in humans have only been possible in the last 2 decades to provide objective documentation for the hypothesis. This paper will review the evidence that conditions such as essential hypertension, congestive heart failure and metabolic syndrome are all accompanied by an increased sympathetic drive, which is likely in all of them to play a pathogenetic role. It will then offer examples showing that sympathetic influences are directly involved in the progression of organ damage associated with these conditions. Finally, evidence will be presented that a maximum degree of sympathetic activation can be seen in end-stage renal failure, in which a relationship between sympathetic activation and clinical outcome has been documented. This has therapeutic implications, which involve the need to use treatments that oppose rather than enhance sympathetic neural activation.