Nebivolol, compared with classical beta-blockers, exerts a high selectivity for beta-adrenergic receptors and also reduces peripheral vascular resistance by modulating nitric oxide (NO) release. This dual mechanism of action leads to effective control of blood pressure at a low degree of beta-blockade and explains the lack of any interference with lipid metabolism. For the same reason, the tolerability profile of nebivolol is highly favorable compared with the classical beta-blockers, with less fatigue and dyspnea in hypertensive subjects, and with an improvement of functional capacity and exercise tolerance in patients with left ventricular dysfunction. Furthermore, contrary to atenolol and propranolol, nebivolol does not diminish specific airway conductance. Compared with other first-line antihypertensive agents, nebivolol was shown to be better tolerated than nifedipine and enalapril, and to have a positive effect on general wellbeing. Among the currently available antihypertensive drugs, nebivolol therefore appears to have a most alteractive safety and tolerability profile, which can be attributed to its NO-mediated effects allowing effective control of hypertension at a lower degree of beta-blockade than with first-generation beta-blockers.