The application of physico-chemical principles has been routinely used to explain various physiological concepts. The Nernst equation is one example of this, used to predict the potential difference created by the transmembrane ion gradient resulting from uneven ion distribution within cellular compartments and the interstitial space. This relationship remains of fundamental importance to the understanding of electrical signaling in the brain, which relies on current flow across cell membranes. We describe four distinct occasions when the Nernst equation was ingeniously applied in experimental design to illuminate diverse cellular functions, from the dependence of the action potential on Na[superscript +] influx to K[superscript +] buffering in astrocytes. These examples are discussed with the aim of inspiring students to appreciate how the application of seemingly textbook-bound concepts can dictate novel experimental design across physiological disciplines.