Alpha2-adrenergic receptors (α2-ARs) bind to their endogenous ligands, epinephrine and norepinephrine, and are blocked by the antagonist yohimbine. There are three subtypes of α2-AR, encoded by three independent, intronless genes. The lack of truly specific ligands for each of the α2-AR subtypes, particularly antagonists, has prevented the unequivocal assignment of the differing α2-AR subtypes to various physiological responses. Despite the similarity of the signaling pathways of the α2-AR subtypes, there are interesting differences in the trafficking itineraries of these receptors. Whereas the α2A- and α2B-AR subtypes are enriched on the surface at steady state, the α2C-AR is distributed between the surface and intracellular compartments. Genetic association studies have linked α2-AR polymorphisms with a number of disease states and variations in drug responses in human populations. For example, α2A-AR polymorphisms have been linked to increased risk of ADHD, hypertension and type 2 diabetes. Additionally, genetic variants in all three subtypes have been associated with various forms of cardiovascular dysfunction. © 2012 Elsevier Inc. All rights reserved.