Essential hypertension is one of the most common disorders that underpin significant morbidity and mortality; however, underlying mechanisms remain elusive that either dictate the actions of individual quantitative trait loci (QTLs) or engineer the overall genetic architecture from them. Recent experimental evidence has unveiled that the genetic architecture determining blood pressure (BP) is assembled from QTL-building blocks by epistasis into regulatory hierarchies. BP, a polygenic and quantitative trait, is homeostasized via pathways participated by Mendelian constituents that operate distantly from end-phase physiological genes. Epistasis genetics performed in the current article has mechanistically unravelled the order and regulatory relationships between certain BP QTLs, and is the first study ever conducted in a mammalian system in analysing a complex trait. The elucidation of the sequence of event and regulatory hierarchies of QTL actions in these pathways will facilitate mechanism-based diagnoses and cause-driven treatments for essential hypertension.