The family of α2-adrenergic receptors (α2-ARs) comprises three subtypes which are each endowed with specific functions. α2-agonists and α2-antagonists are part of the clinician armamentarium since several decades; however, none of the compounds so far available is subtype selective. For long, clonidine and yohimbine have been used for the treatment of hypertension and impotence respectively, but both have been superseded by newer drugs. This review attempts, by a comprehensive analysis of the literature, to cover the present clinical use and the potential therapeutic interest of α2-agonists or antagonists. From the clinical data, it is concluded that, with the exception of a few particular situations, α2-agonists are only of limited utility as a monotherapy. By contrast, they offer several powerful advantages when used in adjunctive therapy. In perioperative settings, α2-agonists are extremely valuable adjuncts to anesthetics and analgesics for the induction of anxiolysis, maintenance of sedation, management of pain and prevention of shivering. In the ophthalmic clinic, they are used to lower intra-ocular pressure during laser surgery of the eye. As a daily medication, α2-agonists are also of interest for the treatment of glaucoma, muscle spasticity, opiate withdrawal, and behavior disorders. The a2-antagonists are useful antidotes for reversing the threatening effects of agonist overdose, but currently there are very few indications. New applications are under investigation, and new molecules with more refined subtypeselectivity may emerge, so the clinical utility of both α2-agonists and antagonists will undoubtedly expand in the future.