DNA lesions that evade repair can lead to mutations that drive the development of cancer, and cellular responses to DNA damage can trigger senescence and cell death, which are associated with ageing. In the kidney, DNA damage has been implicated in both acute and chronic kidney injury, and in renal cell carcinoma. The susceptibility of the kidney to chemotherapeutic agents that damage DNA is well established, but an unexpected link between kidney ciliopathies and the DNA damage response has also been reported. In addition, human genetic deficiencies in DNA repair have highlighted DNA crosslinks, DNA breaks and transcription-blocking damage as lesions that are particularly toxic to the kidney. Genetic tools in mice, as well as advances in kidney organoid and single-cell RNA sequencing technologies, have provided important insights into how specific kidney cell types respond to DNA damage. The emerging view is that in the kidney, DNA damage affects the local microenvironment by triggering a damage response and cell proliferation to replenish injured cells, as well as inducing systemic responses aimed at reducing exposure to genotoxic stress. The pathological consequences of DNA damage are therefore key to the nephrotoxicity of DNA-damaging agents and the kidney phenotypes observed in human DNA repair-deficiency disorders. The DNA damage response is essential to genomic stability. Here, the authors discuss DNA damage-induced nephrotoxicity and kidney cancer, and the essential role of DNA repair in kidney homeostasis, as well as its potential to contribute to kidney dysfunction, including the links between DNA damage, cell-cycle control and ciliopathies. Key points: DNA damage has an important role in the functional decline of tissues associated with ageing, and DNA damage that evades repair can also lead to mutations that drive the development of cancer. The kidney is exquisitely sensitive to chemotherapeutic and environmental agents that damage DNA, leading to both acute and chronic kidney injury. An unexpected and currently incompletely understood link between kidney ciliopathies and the DNA damage response has emerged. Genetic DNA repair defects in humans have highlighted DNA crosslinks, DNA breaks and transcription-blocking damage as particularly toxic lesions to the kidney. Advances in mouse genetic tools, kidney organoids and single-cell RNA sequencing have been instrumental in clarifying how specific kidney cell types respond to DNA damage. DNA damage in kidney cells adversely affects the local microenvironment and elicits systemic responses through signalling pathways that are engaged to potentially reduce tissue exposure to genotoxic stress. [ABSTRACT FROM AUTHOR]