The three alpha2-adrenergic receptor (alpha2AR) subtypes, all of which couple to multiple effectors via Gi/Go proteins, perform various functions, including the mediation of decreases in adenylyl cyclase activity, activation of receptor-mediated K+ channels, and inhibition of voltage-gated Ca2+ channels. The alpha2ARs are polarized in many target cells, such as neurons in the peripheral and central nervous system and in intestinal and renal epithelia. Precise targeting and polarization of molecules are crucial for many physiological processes, and may confer a degree of specificity that, in the case of the adrenergic receptors, could represent a reasonable strategy by which catecholamines coordinate cellular function in a highly specific way. Receptors also redistribute in response to agonist occupancy by means of sequestration, endocytosis, recycling, or, alternatively, down-regulation (degradation). The focus of this review is to compare the similarities and differences among the three alpha2AR subtypes in terms of specificity, signaling, and trafficking. It is anticipated that a molecular understanding of receptor trafficking will lead to novel therapeutic strategies for diseases linked to aberrant adrenergic receptor function or localization.