A couple friends and I are currently doing a space adventure game similar to Starflight I & II, Star Control II, etc.
The story involves a space-fairing Human Empire that was wiped out thousands of years before the game takes place. The Empire, as it was known, was the dominant power in the local region of space. All of the local alien races were either absorbed into the Empire or disarmed.
It should be noted that despite being called the Empire, this is not "The Empire". It is much closer to The Federation. In general, the Empire was benevolent and well respected by its citizens - both Human and alien. The only groups to really oppose the Empire at all were the races forced to disarm after refusing membership in the Empire, but even they don't have much issue with it; other than having their weapons taken away and being monitored for arms development, the Empire left them well enough alone.
The Empire existed as the dominant power for thousands of years, with it's heart centered around Sol and the Earth. Every member race had a voice in government through locally elected governors. Although the Emperor/Empress technically had final authority on all issues, they rarely intervened, preferring to let each nation/planet/system rule itself as fit, following a simple set of guidelines laid out for them.
In its current state, the game takes place in a 1000 x 1000 grid with a little over 900 star systems, and an average of five planets each. Of these, the Empire directly controlled around 200-300 stars at its height. Most of the other stars were ruled through their member races. The Empire was based roughly around the center of the game map on Earth.
The player's race, just getting into space and exploring, is located near one border of the Old Empire. The other races are on mostly on the far side of the Old Empire, and do not travel through that space due to its being "haunted". No one knows how Humanity got obliterated, and it's not worth risking wandering in there.
About 7000 years before the game takes place, the Empire was attacked without any warning by an alien race previously unseen in this region of the galaxy.
In a matter of weeks, the Empire crumbled as world after world was destroyed mercilessly. Despite having the best ships and crews available, the Royal Fleet was completely outgunned and suffered constant defeats. Thousands of Imperial ships were lost, with only a few alien vessels destroyed. When the aliens quickly made it to Earth, the Royal Fleet made one last stand and then helplessly watched the Earth get bombed.
During this time, only Humans were targeted. Initially some other member races tried to provide shelter to refugees, but the aliens almost immediately found these places and destroyed them. Following this, no one would accept Human refugees running from the carnage facing the Empire.
As quickly as they appeared, these unknown aliens departed. The entire Human race was wiped out, but all other local species were left (mostly) unscathed.
Thousands of years later, however, these aliens return. This is around the time the game starts, and is where we've drawn a blank. After such a massively overwhelming victory, why would a race just up and leave if they're planning to come back later to wipe out everyone?
I should point out here that this game, like many other works (Star Trek, for example), is meant to tell a Human tale. As such, we can assume that these aliens have Human motives. Let us also assume that it's not a result of something internal; they aren't fighting a civil war or anything.