Background <p>Resistant hypertension (RHT) is a challenging clinical condition characterized by persistently elevated blood pressure despite adherence to lifestyle modifications and the use of at least three antihypertensive agents, including a high-dose diuretic. RHT is a heterogeneous condition, influenced by multiple pathophysiological mechanisms such as sodium retention, sympathetic overactivity, and vascular dysfunction. Among these, hyperaldosteronism plays a pivotal role in a subset of patients.</p> Methods <p>This systematic review examines in depth the pharmacokinetic properties of aldosterone synthase inhibitors (ASIs), with a focus on their therapeutic potential in patients with RHT. A comprehensive literature search was conducted to identify clinical trials and pharmacological studies investigating ASIs, including baxdrostat, dexfadrostat, lorundrostat, LY3045697, and osilodrostat (LCI699).</p> Results <p>ASIs have shown compelling efficacy in lowering both office-based and 24-h ambulatory blood pressure, particularly in patients with elevated aldosterone levels. These findings underscore the critical role of aldosterone-mediated mechanisms in the pathophysiology of RHT. The inhibitors differ substantially in their metabolic pathways, selectivity profiles, and pharmacokinetic characteristics.</p> Conclusions <p>Emerging data support the potential of ASIs as a therapeutic option for RHT, particularly when treatment is individualized based on renal function, dietary sodium intake, and comorbidities. Personalized treatment strategies may enhance efficacy, improve tolerability, and support durable blood pressure control in this difficult-to-treat population.</p> Registration <p>PROSPERO identifier number CRD42024522918</p> <p>[Graphical abstract available]</p> Graphical Abstract <p></p>