Renal tubular cells that are lethally injured after an acute ischemic or nephrotoxic insult to the kidney can die by necrosis or apoptosis. Necrosis is usually the result of overwhelming and severe cellular ATP depletion. In contrast, there are many potential causes of apoptosis in acute renal failure (ARF). These include cytotoxic events not severe enough to induce necrosis, a relative deficiency of renal growth factors, and loss of cell-matrix or cell-cell adhesive interactions. In some situations, receptor-mediated events induced by tumor necrosis factor-alpha (TNF-alpha) or Fas (CD95) may play a role in apoptosis in ARF. Necrosis and apoptosis are distinct morphologically and biochemically. Necrosis results in an early loss of plasma membrane integrity, the release of injurious substances from the cytosol, and an inflammatory reaction in the surrounding tissue that is readily detected morphologically. In contrast, apoptosis is characterized by progressive cell shrinkage with condensation and fragmentation of nuclear chromatin. Apoptotic cells ultimately break up into plasma membrane-bound vesicles called "apoptotic bodies" that are rapidly phagocytosed by macrophages and neighboring epithelial cells. In experimental models of ARF in vivo, apoptosis of renal tubular cells has been shown to occur in two distinct phases. The first phase of apoptosis occurs early on, between 12 and 48 hours after the acute ischemic or nephrotoxic insult. The second phase of apoptosis occurs many days later, during the recovery phase of ARF. Tubular cell apoptosis occurring shortly after the acute insult probably contributes to tubular cell loss and the tubular dysfunction associated with ARF. In contrast, the apoptosis associated with the recovery phase has been postulated to contribute to the remodeling of injured tubules and to facilitate their return to a normal structural and functional state. Therapeutic interventions that inhibit or promote apoptosis of renal tubular cells have the potential for minimizing renal dysfunction and accelerating recovery after ARF.