The size of the movement and the molecular identity of the moving parts of the voltage sensor of a voltage-gated ion channel are debated. In the helical-screw model, the positively charged fourth transmembrane segment S4 slides and rotates along negative counter charges in S2 and S3, while in the paddle model, S4 carries the extracellular part of S3 (S3b) as a cargo. By introducing pairs of cysteines in S3b and S4 we show that S4 slides 16–26 Å along S3b. These data are not compatible with the voltage-sensor-paddle model, but support the helical-screw model. Knowing the voltage sensor mechanism we can analyze substances affecting excitability at a molecular level. Polyunsaturated fatty acids (PUFAs) have beneficial effects on epileptic seizures and cardiac arrhythmia. We have found that w-3 and w-6 all-cis-PUFAs affect the voltage dependence of a K channel by attracting the voltage sensor S4 to an extracellular position, thereby opening the channel. Our data suggests that fatty acid tails with two or more cis double bonds are required to place the negative carboxylate charge of the PUFA in a position to affect the channel's voltage dependence. We propose that charged lipophilic compounds could play a role in regulating neuronal excitability by electrostatically affecting the channel's voltage sensor. This provides a new approach for pharmacological treatment which is voltage sensor pharmacology