Cilnidipine is a unique Ca2+ channel blocker with an inhibitory action on the sympathetic N-type Ca2+ channels, which is used for patients with hypertension in Japan. Cilnidipine has been clarified to exert antisympathetic actions in various examinations from cell to human levels, in contrast to classical Ca2+ channel blockers. Furthermore, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in clinical practice or animal examinations. After the introduction of nifedipine as an antihypertensive drug, many Ca2+ channel blockers with long-lasting action for blood pressure have been developed to minimize sympathetic reflex during antihypertensive therapy, which have been divided into three groups; namely, first, second, and third generation based on their pharmacokinetic profiles. Since cilnidipine directly inhibits the sympathetic neurotransmitter release by N-type Ca2+ channel-blocking property, the drug can be expected as fourth generation, providing an effective strategy for the treatment of cardiovascular diseases.