Depigmentation therapy is a viable treatment option for patients with extensive vitiligo, particularly those with >50% body surface area involvement, in patients who fail to respond to repigmentation protocols, and those who have obvious cosmetic disfigurement due to patchy pigmentated areas seeking a uniform skin tone. Counseling of the patient holds utmost importance and should include detailed information regarding the permanency of this treatment; its cost, duration, and course; adverse effects; and the possibility of repigmentation. Monobenzyl ether of hydroquinone (MBEH) is the key therapy and the only agent approved by the FDA so far, while many other chemical agents and physical therapies have been explored. Other chemical agents include 4-methoxyphenol, 4-hydroxyanisole, phenol, imatinib, imiquimod, and diphencyprone. Physical therapies comprise cryotherapy and lasers like Q-switched ruby, Q-switched alexandrite, and Q-switched Nd:YAG laser. The efficacy of the combination of these therapies has also been demonstrated in the existing literature. In addition to the clinical efficacy, this chapter delves into the safety profiles of these modalities and also addresses their potential adverse effects. Emerging therapies and novel approaches have also been discussed, offering insights into the future of depigmentation in vitiligo management.