The distinctive properties of voltage-gated proton channels (HV) are described with the intention of relating them to the many biological functions of these channels. A brief account of the conception and discovery of proton channels is provided. The unique regulation of channel opening by both voltage and pH is crucial to its biological functions. A substantial fraction of proton channel research involves their involvement in the “respiratory burst” of white blood cells. Proton channels have a symbiotic relationship with NOX2, the phagocyte NADPH oxidase. The activity of both molecules has profound chemical and electrical effects, and both must function for optimal operation of the system. NOX2 is electrogenic, depolarizing the membrane while simultaneously acidifying the cytoplasm. Both of these effects (depolarization and acidification) activate proton channels, whose activity counteracts both the depolarization and the acidification. Eliminating HV channels strongly depresses the respiratory burst, i.e., production of reactive oxygen species (ROS). In some cells their role mirrors that in leukocytes, but the ROS generated is used for signaling rather than for killing pathogens. In other cells, HV channels perform a wide variety of functions, e.g., contributing to cellular pH homeostasis or generating action potentials that trigger the flash in bioluminescent dinoflagellates.