The alpha2-adrenoceptors (alpha2-ARs) are receptors for endogenous catecholamines (norepinephrine and epinephrine) that mediate a number of physiological and pharmacological responses such as hypotension and sedation. Three distinct subtypes, denoted alpha2A-, alpha2B- and alpha2C-AR, have been characterized and cloned. Employment of mutation screening in the study of human populations from various ethnic backgrounds has shown that alpha2-AR genes are polymorphic. The functional and biochemical consequences of these polymorphisms have been analyzed by expressing the wild-type receptors and their respective genetic variants in heterologous systems such as CHO and COS-7 cells. Changes include alteration in G-protein coupling and in agonist-promoted receptor phosphorylation and desensitization. Case-control and population-based studies have shown clinical association with cardiovascular risk. Further investigation of the genetic variants in specialized cells and transgenic animals will provide the molecular basis of cardiovascular disease and may reveal alpha2-AR variants as potential targets for selective pharmacological interventions.