The integrity of the endothelial lining of the vasculature is essential for vascular homeostasis and normal organ function. Endothelial injury or dysfunction has been implicated in the pathogenesis of diverse vascular diseases. Studies in vitro have demonstrated that a wide variety of stimuli can induce programmed cell death (apoptosis) of endothelial cells, and have suggested that apoptosis could be an important mechanism of vascular injury, resulting in vascular leak, inflammation, and coagulation. In this review, we focus on the potential role of endothelial apoptosis in the initiation and progression of inflammatory and immune disorders, reviewing human diseases and in vivo models in which endothelial cell apoptosis has been demonstrated. Although endothelial cell apoptosis is observed in many inflammatory and immune disorders, we find that there is, as yet, only limited experimental evidence demonstrating that it is critical to the pathogenesis of disease.