Summary: Dihydropyridine calcium channel blockers (DHP-CCBs) are a crucial group of antihypertensive drugs used in both, monotherapy, and combination therapy. Alongside beta-blockers, they serve as a cornerstone in the symptomatic treatment of angina pectoris in patients with chronic coronary syndrome, particularly when arterial hypertension is present. While the individual representatives of this class exhibit similar antihypertensive potency, differences in pharmacokinetics and pharmacodynamic profiles lead to distinct clinical outcomes. This disparity becomes particularly evident in terms of side effects, including lower leg swelling, headaches, dizziness, hot flashes, and facial redness, as well as the overall safety-profile. Lercanidipine, among the most recent and highly selective DHP-CCBs, stands out for its lack of negative inotropic effects and its stable, strong, and long-lasting hypotensive effect. Compared to older generation DHP-CCBs, lercanidipine exhibits a relatively lower incidence of side effects, notably ankle edema, likely due to its high lipophilicity and gradual onset of action. Furthermore, unlike many other DHP-CCBs, lercanidipine does not induce reflex sympathetic activation and exerts a vasodilating effect on both afferent and efferent glomerular arterioles. It maintains stable filtration pressure, preventing any deterioration in renal perfusion or decrease in eGFR. Additionally, lercanidipine protects against kidney damage caused by angiotensin II and demonstrates anti-inflammatory, antioxidant, and anti-atherosclerotic properties by enhancing the nitric oxide bioavailability in vascular endothelium. The increased reactivity in medium and small-caliber arteries is associated with regression of structural changes (stiffening) in the microcirculation of hypertensive patients. The effectiveness of lercanidipine has been demonstrated in numerous studies conducted in various subpopulations, regardless of age. In patients with chronic kidney disease and diabetes, the beneficial effect of lercanidipine on the reduction of albuminuria and the improvement of creatinine clearance has been demonstrated. The aim of this brief review is to summarize shortly the efficacy, safety, and tolerability of lercanidipine in the management of hypertension with comorbidities.