Clonidine is classified as an imidazoline and it is the prototypical alpha-2 receptor agonists. It has been used for several years to treat hypertension. It has also been used, “off label”, for a variety of purposes, including opioid and anesthetic sparing effects, anxiolysis and sedation, drug withdrawal as well as stabilizing blood pressure and reducing stress response to surgery. Particularly in the case of patients with overt or underlying cardiac disease and in those at risk of perioperative ischemia the action of clonidine can be expected to reduce the risk of procedure-related cardiac events. In addition, clonidine used as a premedication drug before surgery or surgical procedure, has been shown to substantially reduce anaesthetic, benzodiazepine and opioids requirements. However, its “off label” use, the absence of an intravenous form of in the United States, possible inadvertent hypotension, bradycardia or post-operative sedation, and the variability of the haemodynamic response to different doses or rates of administration, have limited its use in clinical practice. This review discusses the potential role of clonidine and the supporting evidence for the use of this drug beyond its antihypertensive use in perioperative medicine and critical care in adults patients.