This article describes selected historical milestones in the field of neutral ionophore-based sensors, starting with the first discovery by Wilhelm Simon and their impact to analytical sciences despite the initial difficulty to understand their function. The reader is then guided through topics in which the author has been involved over the years, from understanding thermodynamic aspects to the field of non-equilibrium potentiometry, polyion sensors, trace level potentiometry, instrumentally controlled ion sensors and finally potentiometry involving local perturbations and transient currents that allow for new readout possibilities. Discussed applications include clinical diagnostics, environmental in situ sensing/profiling and speciation analysis. The article loosely follows the content of the Simon-Widmer Award lecture of the same title presented by the author at the CH Analysis 2019 conference in Beatenberg, Switzerland.