As a consequence of continuous interaction with mutagens, the genome sequence accumulates changes, which are referred to as "somatic mutations". Somatic variants acquired by normal cells during a lifetime are difficult to detect with common sequencing methods. This review provides a basic description of currently available technologies for somatic mutation detection and summarizes the studies that have explored somatic mutation in the kidneys. Given the role of somatic mutations in the formation of kidney cysts, genomic analyses can be used to investigate mechanisms that influence disease progression in inherited cystic kidney disorders. Moreover, genomic analyses are an important method to explore the evolution from a normal cell to cancer, providing insights into mechanisms of tumor initiation. Somatic mutation data can be used to discover endogenous and exogenous mutagens that harness the kidneys, including tobacco and aristolochic acid. In addition, genomic analyses have highlighted a link between kidney damage and mutation. This information is going to be key for understanding life-style factors that influence kidney cancer risk, overall impacting clinical decisions and public health strategies.