High concentrations of extracellular phosphate are toxic to cells. Impaired urinary phosphate excretion increases serum phosphate level and induces a premature-ageing phenotype. Urinary phosphate levels are increased by dietary phosphate overload and might induce tubular injury and interstitial fibrosis. Extracellular phosphate exerts its cytotoxic effects by forming insoluble nanoparticles with calcium and fetuin-A; these nanoparticles are referred to in this Review as calciprotein particles. Calciprotein particles are highly bioactive ligands that can induce various cellular responses, including the osteogenic transformation of vascular smooth muscle cells and cell death of vascular endothelial cells and renal tubular epithelial cells. Calciprotein particles are detected in the serum of animal models of kidney disease and in patients with chronic kidney disease (CKD) and might be associated with a (mal)adaptation of the endocrine axes mediated by fibroblast growth factors and Klothos that regulate phosphate homeostasis and ageing. These observations raise the possibility that calciprotein particles contribute to the pathogenesis of CKD. This theory, if verified, is expected to provide novel diagnostic markers and therapeutic targets in CKD.