The ability of the kidney to regenerate successfully after injury is lost with advancing age, chronic kidney disease and after irradiation. The factors responsible for this reduced regenerative capacity remain incompletely understood, with increasing interest in a potential role for cellular senescence in determining outcomes after injury. Here, we demonstrated correlations between senescent cell load and functional loss in human aging and chronic kidney diseases including radiation nephropathy. We dissected the causative role of senescence in the augmented fibrosis occurring after injury in aged and irradiated murine kidneys. In vitro studies on human proximal tubular epithelial cells, and in vivo mouse studies demonstrated that senescent renal epithelial cells produced multiple components of the senescence associated secretory phenotype including transforming growth factor beta-1, induced fibrosis and inhibited tubular proliferative capacity after injury. Treatment of aged and irradiated mice with the B-cell lymphoma (Bcl) 2/w/xL inhibitor ABT-263 reduced senescent cell numbers and restored a regenerative phenotype in the kidneys with increased tubular proliferation, improved function and reduced fibrosis after subsequent ischaemia-reperfusion injury. Senescent cells are key determinants of renal regenerative capacity in mice and represent emerging treatment targets to protect aging and vulnerable kidneys in man.