The human sympathetic nervous system has an important regulatory role. In its dysfunctional hyperexcitatory state, it can lead to multiple pathologies. The renal sympathetic nerves play a significant role in these pathological states. Percutaneous renal sympathetic denervation (RSDN) allows for safe minimally invasive selective denervation of the renal sympathetic nerves. RSDN has been shown to be safe and efficacious in blood pressure reduction in earlier nonblinded SYMPLICITY HTN-1 and -2 trials. In Europe, it is approved for a select group of truly resistant severe essential hypertension. However, its real efficacy is now in doubt with the blinded SYMPLICITY HTN-3 trial that showed no significant difference in change in office and mean 24-h ambulatory systolic blood pressure between RSDN and sham-procedure arms. This review will look at the potential targets for percutaneous RSDN-heart failure, cardiac arrhythmias and kidney disease, sleep-disordered breathing and insulin resistance.