When kidneys are injured in vivo, the reaction of the renal epithelial is heterogeneous. Some cells, especially those of the proximal tubule, undergo necrosis, other cells undergo apoptosis, and still others survive the injury apparently intact. In addition, injured tubules are relined with new cells actively engaged in DNA synthesis. Nephrotoxic and ischemic renal damage also is accompanied by a typical immediate early gene (IEG) response, which does not always occur in cells that undergo DNA synthesis, suggesting that the role of the IEG response is not necessarily proliferative in this setting. The activation of parts of this pathway is mediated by the stress-activated protein kinases (SAPKs), which may induce cell-cycle arrest and apoptosis. Downregulation of the SAPKs improve renal function and improve long-term outcome during ischemic renal failure. It is thus possible that manipulation of this pathway could ameliorate acute renal failure. Clues to the pertinent pathways and genes to target therapy to alter the course of renal failure will come from continued understanding of the transduction pathways activated by renal cell stress and the identification of factors that promote survival of renal cells.