Summary: Resistant hypertension remains a major clinical challenge and is associated with an increased risk of cardiovascular events, heart failure, and mortality. Despite the availability of contemporary antihypertensive treatment strategies, a substantial proportion of patients fail to achieve recommended blood pressure targets. The aim of this paper was to present the role of clonidine in the management of resistant hypertension based on current guidelines and literature data, supplemented by two illustrative case reports. Clonidine is a centrally acting antihypertensive agent that stimulates α2-adrenergic and imidazoline receptors, leading to suppression of sympathetic nervous system activity and effective blood pressure reduction. The presented clinical cases included a 65-year-old woman with severe resistant hypertension and a 58-year-old man with persistently elevated blood pressure despite multidrug therapy. In both patients, the addition of clonidine resulted in adequate blood pressure control and clinical improvement. Evidence from the ReHOT trial and recent network meta- -analyses indicates that clonidine provides antihypertensive efficacy comparable to spironolactone in patients with resistant hypertension. Clonidine may therefore represent a valuable alternative or adjunctive treatment option, particularly in individuals with increased sympathetic activity, chronic kidney disease, obesity, or anxiety-related blood pressure elevation. The presented cases further support the effectiveness and practical utility of clonidine in everyday clinical practice and highlight its potential role in overcoming therapeutic resistance.