Renal sympathetic denervation (RSD) appears to hold promise as a non-pharmacological means for reducing blood pressure (BP). A variety of novel approaches are under investigation in clinical trials, including radiofrequency and ultrasound-based technologies. Catheter-based sympathetic denervation of the renal arteries using minimally invasive endovascular approaches has been under investigation in clinical trials since 2009. Initial studies were limited in that they were non-randomized, without sham control, and small in size. The large, randomized, blinded, sham-controlled SYMPLICITY HTN-3 trial, which attempted to account for many of these limitations, failed to show significant improvement in BP control. Post hoc analyses of that trial suggested that inclusion of patients with isolated systolic hypertension, completeness of denervation, and variation in medication adherence may have contributed to the absence of BP reduction. Subsequent sham-controlled trials were designed with more attention to patient selection and procedural technique. Collectively, these small, second-generation sham-controlled trials demonstrated short-term reductions in ambulatory BP without any concomitant significant safety concerns in both medication-naive and medication-treated hypertensive patients. In a meta-analysis of 6 published randomized, sham-controlled trials of RSD (n=977), we confirmed the safety and efficacy of RSD, findings which were largely driven by results from second-generation trials. External delivery of ultrasound energy has also been investigated as a means to denervate the renal arteries but has not been evaluated alongside catheter-based technologies in prior studies.