The rat has classically been the species of choice for pharmacological and toxicological investigations during the early in vivo phase of drug discovery, providing high-quality physiological datasets on cardiovascular and renal pathophysiology over many decades. Recent genome engineering advances, particularly with zinc finger nucleases and CRISPR/Cas9, are now enabling us to measure these typically challenging physiological studies in gene-targeted strains, previously restricted to murine models. This presentation will focus our acquired understanding of rat models of hypertension, diabetic nephropathy, and acute and chronic kidney disease. These models have made important contributions to our understanding of cardio-renal diseases, revealing key genetic drivers such as Ace and P2rx7 involved in pathogenic processes. By targeting these genes of interest, we are gaining a better understanding of the aetiology of cardiovascular and renal pathologies, with the promised potential of slowing, or even reversing, disease progression. Some, but not all of the identified targets, have proven to be translationally important. These advances are under intensive investigation in my lab to identify new druggable targets and develop targeting strategies.