Apoptotic cell death is usually a response to the cell microenvironment. Apoptosis requires the activation of lethal molecules and the inactivation of prosurvival ones. Both are potential therapeutic targets. Apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury. Apoptotic pathways that are active in glomerular and tubular epithelium include death induced by survival factor deprivation, death receptor activation, mitochondrial injury, endoplasmic reticulum stress, lysosomal destabilization, and caspase cascade activation. These pathways are not mutually exclusive, and stimulus-specific differences in the recruitment of apoptotic pathways have been observed. In some cases, the activation of a certain death pathway is redundant, and its inhibition does not prevent eventual cell death. This review summarizes recent advances in the field and discusses the rational basis to choose from the available tools to target apoptosis therapeutically.