Hypertension is a complex trait that is influenced by both heritable and environmental factors. The search for genes accounting for the susceptibility to hypertension has driven parallel efforts in human research and in research using experimental animals in controlled environmental settings. Evidence from rodent models of genetic hypertension and human Mendelian forms of hypertension and hypotension have yielded mechanistic insights into the pathways that are perturbed in blood pressure homeostasis, most of which converge at the level of renal sodium reabsorption. Yet, the bridging of evidence from these very diverse approaches to identify mechanisms underlying hypertension susceptibility and the translation of these findings to human populations and public health remain a challenge. Furthermore, findings from genome-wide association studies still require functional validation in experimental models. In this review, we highlight results and implications from key studies in experimental and clinical hypertension to date.