Genetic studies into rare inborn errors of renal tubular sodium handling in man have brought many interesting, sometimes surprising insights into how we can maintain our bodies’ electrolytes and fluids homeostasis. The cloning and identification of sodium transporting genes and proteins like NHE3, NKCC2, ROMK, CLCNKB, NCC, and EnaC has considerably improved our understanding of renal salt handling. Subsequently, studies of genetically engineered animals provided even more insight into the complex renal physiology. The recent discovery of the WNK kinases as regulators and integrators of specific renal transport pathways helped elucidate this further and lets us start to appreciate the full complexity of renal sodium handling. We summarize recent findings in the field in the context of human diseases and a pathophysiologic basis for their treatment.