In humans and experimental models of renal ischemia, tubular cells in various nephron segments undergo necrotic and/or apoptotic cell death. Various factors, including nucleotide depletion, electrolyte imbalance, reactive oxygen species, endonucleases, disruption of mitochondrial integrity, and activation of various components of the apoptotic machinery, have been implicated in renal cell vulnerability. Several approaches to limit the injury and augment the regeneration process, including nucleotide repletion, administration of growth factors, reactive oxygen species scavengers, and inhibition of inducers and executioners of cell death, proved to be effective in animal models. Nevertheless, an effective approach to limit or prevent ischemic renal injury in humans remains elusive, primarily because of an incomplete understanding of the mechanisms of cellular injury. Elucidation of cell death pathways in animal models in the setting of renal injury and extrapolation of the findings to humans will aid in the design of potential therapeutic strategies. This review evaluates our understanding of the molecular signaling events in apoptotic and necrotic cell death and the contribution of various molecular components of these pathways to renal injury.