Essential hypertension is a common disorder that leads to significant morbidity and mortality; however, the underlying mechanisms have remained elusive. Recent animal model studies have uncovered a complex genetic architecture of quantitative trait loci (QTLs) for blood pressure (BP), intricate QTL-QTL interactions and powerful genome regulations that underlie polygenic hypertension. BP, a quantitative trait manifesting as a continuous variation, seems to be controlled by individual 'monogenic' QTLs following Mendelian inheritance. Certain QTLs are functionally organized in epistatic modules that likely participate in pathways and cascades, whereas others belong to independent modules. This understanding provides insights into probable genetic mechanisms underlying essential hypertension. Translation of gene discovery to therapy will require an integrated approach that includes experimental validation of genes in animal models and in humans.