—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.