Recent studies demonstrated that selective intra-thalamic block of the Kv1.2 potassium channels rapidly reverses the unconsciousness of inhalational anesthesia (Alkire et al., 2009). Furthermore, intra-thalamic block of Kv1.3 with selective blocker, ShK, reverses the unconsciousness effect of sevoflurane. Both findings suggestthat Shaker-related potassium channels might be key targets for anesthetics. We tested this hypothesis using patch clamp recordings of potassium currents in cell lines stably expressing homomeric human Shaker family channels. We found that at low voltages, sub-clinical and clinical doses of sevoflurane irreversibly potentiate potassium current through Kv1.3>Kv1.2>Kv1.5>Kv1.1. channels, by increasing the peak current amplitude and accelerating the current activation kinetics. At higher voltages, clinical doses of sevoflurane inhibit Kv1.4>Kv1.5.>Kv1.3 and potentiate Kv1.2>Kv1.1. Sevoflurane had no effect on lipid bilayer conductance, suggesting direct interaction of the anesthetic with potassium channel subunits. Thus, Shaker potassium channel modulation may contribute to the clinical effects of general anesthesia. Supported by the Hillblom Foundation and NIH 1P01AG032131.