Drugs that target voltage-gated ion channels generally act by blocking the ion-conducting pore or, for some recently developed anti-epileptics, by interacting with the gate that keeps the channel open. An interesting alternative drug target is instead the voltage sensor. This positively charged part of the channel moves in response to changes in membrane potential which induces channel opening or closing. In this work we combine mutagenesis with electrophysiology to show that free polyunsaturated fatty acids (PUFAs) act as potassium-channel openers by a direct interaction with the channel's voltage sensor. Furthermore, we design a channel supersensitive to PUFAs to use for future drug screening. We show that the PUFA-binding site is a novel pharmacological site located at the lipid-facing surface of the voltage-sensor domain. Both the mechanism of action and the binding site for PUFA is unique and do not overlap with those previously reported for other compounds. We believe that our work provides a structural and mechanistic framework for future design of specific gating modifiers that electrostatically target the voltage sensor. Such substances are valuable in the treatment of epilepsy and cardiac arrhythmia. Detailed information on the PUFA – channel interaction is also important for understanding the mechanism of the PUFA-rich ketogenic diet and the antiarrhythmic effect of PUFAs on different voltage-gated ion channels.