K(+) channels are important regulators of arterial tone by providing membrane hyperpolarization and thus counteracting the activity of voltage-gated Ca(2+) channels in the smooth muscle and, thus, vasoconstriction. The endothelium and smooth muscle express a variety of different K(+) channels, such as Ca(2+)-activated K(+) channels (KCa), voltage-gated (KV), two-pore-domain (K2P), and inward rectifying (KIR) and KATP channels. Their contributions to the numerous mechanisms of endothelium-dependent and smooth muscle-dependent relaxation are closely related to their electrophysiological properties, activation mechanisms, and to differential expressions pattern within the vascular wall. Here, we summarize the cardiovascular phenotypes in murine models of genetic K(+)-channel deficiency and focus, in particular, on defective vasoregulation in mice deficient of endothelial Ca(2+)-activated K(+) channels, IK (KCa3.1) and SK (KCa2.3), and smooth muscle Ca(2+)-activated K(+) channels, BK (KCa.1.1). Genetic deficiency of endothelial IK and SK severely impairs the endothelium-derived hyperpolarization-mediated type of arterial dilation. Moreover, SK deficiency impairs NO-mediated dilator responses, thus indicating subtype-specific actions in endothelial function. Loss of IK and/or SK channels is associated with sizeable higher blood pressure. In contrast, genetic deficiency of smooth BK channels enhances arterial blood pressure which is linked to mainly a loss of spontaneous transient outward currents in the smooth muscle cells as well as renal and adrenal gland functions (hyperaldosteronism). In conclusion, genetic deficiency of vascular K(+) channels results in severe impairments of local and systemic blood pressure regulation. These alterations strengthen the perspective that vascular K(+) channels are potential pharmacologic targets for improvement of vasodilator functions in cardiovascular pathologies.