Vascular endothelial cells normally perform several key homeostatic functions such as keeping blood fluid, regulating blood flow, regulating macromolecule and fluid exchange with the tissues, preventing leukocyte activation, and aiding in immune surveillance for pathogens. Injury or cell death impairs or prevents conduct of these activities, resulting in dysfunction. Most endothelial cell death is apoptotic, involving activation of caspases, but nonapoptotic death responses also have been described. Stimuli that can cause endothelial injury or death include environmental stresses such as oxidative stress, endoplasmic reticulum stress, metabolic stress, and genotoxic stress, as well as pathways of injury mediated by the innate and adaptive immune systems. Pathways of immune-mediated death include those activated by death receptors as well as those activated by cytolytic granules and reactive oxygen species. The biochemical pathways activated by these injurious stimuli are described herein and will serve as a basis for future development of endothelial protective therapies.