The salt-sensitive Dahl S (SS) rat model and genetically engineered variations of this model have been used to understand the regulation of cardiovascular phenotypes associated with the complex disease of hypertension. Building upon our initial development of the first genomic scale map of determinants of cardiovascular and renal function, molecular genetic technologies including microarray, DNA and RNA sequencing and proteomics have been applied to understand mechanisms that determine blood pressure, salt-sensitivity and renal injury. Studies are based upon the overall concept that a causal gene may impact on one or more intermediate molecular pathways which both diverge and converge to form larger tree-like branches or intermediate physiological pathways ultimately determine blood pressure. We began identifying such pathways related to kidney function by studying whole organ function and whole tissue gene expression searching for differences in SS and salt-resistant normotensive control strains. Studies then moved from whole tissue analyses (containing many cell types) to a focus on a single kidney cell type, the medullary thick ascending limb of Henle (mTAL). Our physiological studies have confirmed the mTAL as a major site of the excess O2- and H2O2 production which together with reduced bioavailability of NO contributes importantly to the reduced medullary blood flow, sodium retention, hypertension, and renal injury found in the outer medulla of the SS rat. Transcriptome profiles, RNAseq and microRNA sequencing, together with Bayesian model analysis of mTAL epithelial cells, have begun to reveal novel genes, microRNAs and regulatory pathways responsible for altered function and renal injury of SS rats. LC/MS proteomic techniques have identified differentially expressed proteins in mTAL mitochondria which point to deficiencies of mTAL energy production and oxygen utilization in SS rats contributing to salt-induced hypertension and renal medullary oxidative stress. We have recently developed a rat model with a null mutation of p67phox on the SS background using Zinc Finger Nuclease (ZFN) technology and found the p67phox cytosolic subunit of NAD(P)H oxidase in the mTAL contributes importantly to the excess free radical production in this nephron segment. ZFN technology has now enabled us to reveal functional relevance of candidate genes found to be associated with hypertension in human GWAS studies.