Human studies, conducted in the presence of clinical conditions characterized by endothelial dysfunction, evidenced that endothelial cells, in response to different agonists and physical stimuli, become a source of endothelium-derived contracting factors (EDCFs), mainly cyclooxygenase (COX)-derived prostanoids. Their production has been documented in several human diseases, mostly in essential hypertension and aging. The EDCF production was at first identified as responsible for impaired endothelium-dependent vasodilation in the forearm microcirculation of patients with essential hypertension. Subsequent studies demonstrated that COX-dependent EDCF products are also a characteristic of the aging process, and essential hypertension seems to only anticipate the phenomenon. Of note, in aging and hypertension, both indomethacin, a COX inhibitor, and vitamin C, an antioxidant, totally reverse the blunted vasodilation to acetylcholine by restoring NO availability, thus suggesting that EDCFs could be one of the major sources of oxygen free radicals. The presence of EDCFs was documented also in other clinical setting, such as coronary artery disease and estrogen deprivation. In conclusion, many human pathological conditions characterized by a decline in endothelial function are associated with a progressive decrease in NO bioavailability and increase in the production of EDCFs. The mechanisms that regulate the balance between NO and EDCFs and the processes transforming the endothelium from a protective organ to a source of vasoconstrictor, proaggregatory and promitogenic mediators, remain to be determined.