Several years ago the hypothesis was advanced that alterations of endothelial function could explain much of the pathophysiology of preeclampsia. Since that time, extensive data have been generated to support the hypothesis. Markers of endothelial activation can be demonstrated in women with overt preeclampsia. More importantly, many of these markers precede clinically evident disease and disappear with resolution of the disease. The original postulate was that materials produced by the poorly perfused placenta, which is characteristic of preeclampsia, entered the systemic circulation and altered endothelial cell activity. This was proposed to change vascular sensitivity to circulating pressors, activate coagulation, and reduce vascular integrity resulting in the pathophysiological changes of preeclampsia. As data have accumulated it has become increasingly evident that the insult to the endothelium is neither toxicity nor nonspecific injury but rather can better be characterized as endothelial activation. Candidate molecules have been suggested but not established. It seems likely that the responsible agent(s) will not be unique molecules but rather usual present in excessive amounts. The hypothesis has been expanded to invoke involvement of the maternal constitution in the generation of endothelial injury and injurants. This concept is stimulated by the observation that reduced placental perfusion per se is not sufficient to generate the maternal syndrome. Women with growth-restricted fetuses frequently are not preeclamptic. Placental bed biopsies from not only growth-restricted but also prematurely born infants demonstrate failure of the physiological remodeling of decidual vessels responsible for the reduced placental perfusion of preeclampsia. This has led to the concept that preeclampsia is secondary to an interaction of reduced placental perfusion and maternal factors. Interestingly these maternal factors, obesity, insulin resistance, black race, hypertension, and elevated plasma homocysteine concentration are all risk factors for atherosclerosis in later life.