Potassium ion (K(+)) channel activity is a major regulator of vascular muscle cell membrane potential (E(m)) and is therefore an important determinant of vascular tone. There is growing evidence that the function of several types of vascular K(+) channels is altered during major cardiovascular diseases, such as chronic hypertension, diabetes, and atherosclerosis. Vasoconstriction and the compromised ability of an artery to dilate are likely consequences of defective K(+) channel function in blood vessels during these disease states. In some instances, increased K(+) channel function may help to compensate for increased vascular tone. Endothelial cell dysfunction is commonly associated with cardiovascular disease, and altered activity of nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor could also contribute to changes in resting K(+) channel activity, E(m), and K(+) channel-mediated vasodilatation. Our current knowledge of the effects of disease on vascular K(+) channel function almost exclusively relies on interpretation of data obtained by using pharmacological modulators of K(+) channels. As further progress is made in the development of more selective drugs and through molecular approaches such as gene targeting technology in mice, specific K(+) channel abnormalities and their causes in particular diseases should be more readily identified, providing novel directions for vascular therapy.