Recent technical advances have renewed interest in device-based therapy for the treatment of drug-resistant hypertension. Findings from recent clinical trials regarding the efficacy of electrical stimulation of the carotid sinus for the treatment of resistant hypertension are reviewed here. However, a major goal of this article is to summarize experimental studies that have provided a conceptual understanding of the mechanisms that account for the long-term blood pressure lowering of arterial pressure with baroreflex activation. In so doing, the mechanistic insight from these studies may help to identify subsets of this heterogeneous population that stand to benefit the most. In this regard, because clinical, experimental, and theoretical evidence indicates that the kidneys play a dominant role in long-term control of arterial pressure, this article focuses on the mechanisms that link baroreflex-induced reductions in central sympathetic outflow with increases in renal excretory function that lead to sustained reductions in arterial pressure. Despite the encouraging findings from recent clinical trials, more basic research and additional clinical trials are needed to better define the benefit of baroreflex activation therapy in resistant hypertension and in other states of sympathetic activation such as heart failure and advanced renal disease.