Septic shock is associated with life-threatening vasodilation and hypotension. To cause vasodilation, vascular endothelium may release nitric oxide (NO), prostacyclin (PGI2), and the elusive endothelium-derived hyperpolarizing factor (EDHF). Although NO is critical in controlling vascular tone, inhibiting NO in septic shock does not improve outcome, on the contrary, precipitating the search for alternative therapeutic targets. Using a hyperacute tumor necrosis factor (TNF)-induced shock model in mice, we found that shock can develop independently of the known vasodilators NO, cGMP, PGI2, or epoxyeicosatrienoic acids. However, the antioxidant tempol efficiently prevented hypotension, bradycardia, hypothermia, and mortality, indicating the decisive involvement of reactive oxygen species (ROS) in these phenomena. Also, in classical TNF or lipopolysaccharide-induced shock models, tempol protected significantly. Experiments with (cell-permeable) superoxide dismutase or catalase, N-acetylcysteine and apocynin suggest that the ROS-dependent shock depends on intracellular radicals. Potassium channels activated by ATP (K_ATP) or calcium (K_Ca) are important mediators of vascular relaxation. While NO and PGI2-induced vasodilation involves K_ATP and large-conductance BK_Ca channels, small-conductance SK_Ca channels mediate vasodilation induced by EDHF. Interestingly, also SK_Ca inhibition completely prevented the ROS-dependent shock. Our data thus indicate that intracellular and SK_Ca channels represent interesting new therapeutic targets for inflammatory shock. Moreover, they may also explain why antioxidants other than tempol fail to provide survival benefit during shock.