<p>  </p> <p>As our ability to make more sensitive measurements increases, we begin to reach for the ultimate measurement sensitivity: a single entity. Mass spectrometry and fluorescence-based methods exist for single entity studies, and through these the intriguing effects of confinement begin to be observed. These mass spectrometry and fluorescence-based techniques are however, often destructive, which precludes measurements over time. The advent of nanoelectrochemical methods, however, allows for the creation of tools that can make measurements inside of confined volumes—a droplet, a cell, <em>etc</em>.—over extended periods of time. While most nanoelectrochemical methods are based on amperometry or voltammetry, potentiometry allows for minimal perturbation of the system’s homeostasis by passing negligible current.</p> <p>To overcome many of the issues involved in these other methods, we design potentiometric tools that can be easily miniaturized to fit within single entities, particularly within single cells. These tools include enzymatic biosensors designed to be minimally influenced by the cell’s O2 or NAD+ levels, as well as a novel reference electrode that can be made to be very low leakage or completely leakless to avoid contamination of the cell by the reference electrode’s internal filling solution. Both of these tools are designed such that they are easily modified to suit a number of different applications, including for use inside non-aqueous solutions.</p>