The identification of genetic factors associated with the risk, onset, and progression of kidney disease has the potential to provide mechanistic insights and therapeutic perspectives. In less than two decades, technological advances yielded a trove of information on the genetic architecture of chronic kidney disease. The spectrum of genetic influence ranges from (ultra)rare variants with large effect size, involved in Mendelian diseases, to common variants, often non-coding and with small effect size, which contribute to polygenic diseases. Here, we review the paradigm of UMOD, the gene coding for uromodulin, to illustrate how a kidney-specific protein of major physiological importance is involved in a spectrum of kidney disorders. This new field of investigation illustrates the importance of genetic variation in the pathogenesis and prognosis of disease, with therapeutic implications.