Potentials in the positive MV to GV range occur (or are presumed to) up in space. This corresponds to solar wind knocking away electrons preferentially. Likewise, the Sun itself has a pretty high voltage (in terrestrial terms). Neither matters much for overall matter or charge balance, because such a field pretty quickly overcomes the energy pushing it (i.e., MeV of particles in solar wind) and the vast majority of matter remains neutral.
An ion thruster works by ionizing a propellant gas (usually xenon) and accelerating it with as much voltage as possible (usually in the 100k to several meg range). This would leave the craft negative, however, and the charged ions would eventually circle around and return (after travelling a pretty good distance I suspect). Therefore, they also provide an electron gun, of similar voltage level and equal current flow, to shoot electrons into the ion wake and maintain neutrality. Whether the gas ever deionizes, who knows, but as long as it remains neutral (plasma or gas), it's fine.
There is such a concept as potential at infinity, which corresponds to, taking the average over the rest of the universe. This would be "ground" in the most fundamental sense. In almost every other situation, however, "ground" is whatever is a convenient reference. Sometimes it's the Earth's surface, sometimes it's a nearby metal plane or enclosure. Sometimes it's the inside of an enclosure, which externally is at some massive potential against something else!
Voltage is only ever meaningful as a difference.
Tim