Abstract-Human essential hypertension is a complex, multifactorial, quantitative trait under a polygenic control. Several strategies have been developed over the last decade to dissect genetic determinants of hypertension. Of these, the most successful have been studies that identified rare mendelian syndromes in which a single gene mutation causes high blood pressure. The attempts to identify multiple genes, each with a small contribution to the common polygenic form of hypertension, have been less successful. Several laboratories focused their attention on rat models of genetic hypertension, which can be considered as a reductionist paradigm for human disease. Using numerous crosses between hypertensive and normotensive strains, investigators identified several quantitative trait loci (QTL) for blood pressure subphenotypes and for cardiovascular complications such as left ventricular hypertrophy, kidney failure, stroke, and insulin resistance. Furthermore, congenic strains have been produced to confirm the existence of some of these QTL and to narrow down the chromosomal regions of interest. A number of interesting strategies have been developed, including a "speed" congenic strategy perfected by our group in Glasgow. However, the limit of congenic strategy is estimated at 1 cM, which corresponds to 2ϫ10 6 base pairs of DNA and Ϸ50 candidate genes. It is envisaged that gene expression profiling with cDNA microarrays might allow a quick progression toward the gene identification within cardiovascular QTL. In parallel experimental effort, several laboratories have been developing gene transfer/therapy strategies with adenoviral or adeno-associated viral vectors used, for example, to overexpress protective vascular genes such as vascular endothelial growth factor or endothelial nitric oxide synthase. It is anticipated that further developments in positional cloning of susceptibility and severity genes in hypertension and its complications will lead to a direct transfer of these discoveries to essential hypertension in humans and will ultimately produce novel targets for local and systemic gene therapy in cardiovascular disease. Key Words: genes Ⅲ rats Ⅲ stroke Ⅲ endothelium Ⅲ hypertension, essential H uman essential hypertension is a typical example of a complex, multifactorial, and polygenic trait. It is most likely that there are several causal genes, which together contribute to between 30% and 50% of the variation in blood pressure among individuals. 1 These genetic determinants interact with environmental factors such as, for example, dietary salt to produce the final disease phenotype. Despite very significant recent progress in genomic and statistical tools, the genetic dissection of human essential hypertension still provides a major challenge. 2 Three main lines of investigation have been developed so far. These include linkage analysis in families segregating for rare, mendelian forms of hypertension, candidate gene approaches, and genome-wide scanning strategies. Of the above approaches, the search for...