Evidence continues to accumulate on the importance of paracrine substances formed in the endothelium in regulation of the vascular system. Mechanisms that govern the balance between relaxing and contracting factors are important for understanding the regulation of blood vessel tone in health and disease. Chemical antagonism between superoxide anions and nitric oxide has been recognized as a potentially important modulator of vascular reactivity as well as being a source of peroxynitrite, a potent oxidant. In several models of vascular diseases, impairment of endothelium-dependent relaxations and promotion of endothelium-dependent contractions has been ascribed to increased production of superoxide anions. In pathologic conditions, increased production of superoxide anions may be responsible for an impairment of balance between relaxing and contracting factors favoring an increase in arterial tone. In this review the role of superoxide anions in modulation of endothelial mechanisms responsible for regulation of arterial tone will be discussed.