Despite availability of effective drugs for hypertension therapy, significant numbers of hypertensive patients fail to achieve recommended blood pressure levels on ≥3 antihypertensive drugs of different classes. These individuals have a high prevalence of adverse cardiovascular events and are defined as having resistant hypertension (RHT) although nonadherence to prescribed antihypertensive medications is common in patients with apparent RHT. Furthermore, apparent and true RHT often display increased sympathetic activity. Based on these findings, technology was developed to treat RHT by suppressing sympathetic activity with electrical stimulation of the carotid baroreflex and catheter-based renal denervation (RDN). Over the last 15 years, experimental and clinical studies have provided better understanding of the physiological mechanisms that account for blood pressure lowering with baroreflex activation and RDN and, in so doing, have provided insight into which patients in this heterogeneous hypertensive population are most likely to respond favorably to these device-based therapies. Experimental studies have also played a role in modifying device technology after early clinical trials failed to meet key endpoints for safety and efficacy. At the same time, these studies have exposed potential differences between baroreflex activation and RDN and common challenges that will likely impact antihypertensive treatment and clinical outcomes in patients with RHT. In this review, we emphasize physiological studies that provide mechanistic insights into blood pressure lowering with baroreflex activation and RDN in the context of progression of clinical studies, which are now at a critical point in determining their fate in RHT management.