<p>Renal denervation (RDN) has re-entered the therapeutic landscape of hypertension following contemporary sham-controlled trials demonstrating reproducible reductions in blood pressure. However, variability in treatment response remains a defining feature, raising important questions regarding its clinical applicability. Emerging evidence indicates that this heterogeneity is primarily attributable to differences in patient phenotype rather than limitations of device technology. This narrative review synthesizes evidence from randomized trials, meta-analyses, and key observational studies to examine determinants of response to RDN across clinical and mechanistic domains. Particular emphasis is placed on hypertension phenotype, ambulatory blood pressure characteristics, baseline blood pressure levels, medication adherence, sympathetic nervous system activity, renal artery anatomy, and associated comorbid conditions. Available data consistently suggest that patients with sustained hypertension confirmed by ambulatory monitoring, higher baseline blood pressure, and features indicative of sympathetic overactivity derive greater benefit from denervation. In contrast, pseudoresistance, white-coat hypertension, advanced vascular stiffness, and unfavorable anatomical characteristics are associated with attenuated or inconsistent responses. Reinterpretation of contemporary trial data further indicates that the magnitude of blood pressure reduction, although moderate, is clinically meaningful when applied to appropriately selected populations. These findings support a shift toward mechanism-based, phenotype-guided patient selection as a means to reconcile prior inconsistencies, optimize clinical implementation, and inform future research. Within this framework, RDN may be more appropriately positioned as a targeted adjunctive therapy in personalized hypertension management.</p>