A very flexible genre. Strengths include; Technology, Exotic Locations, the Unknown, The strange but known, etc
Several interesting ideas come to mind;
The farthest flung human colony is only recently established. The first generation colonists have been brought out of cryosleep and begun the building of their world. Only a few short years later, an unknown ship enters the system - and they are curious about their 'discovery'!
Themes; Frontier life, Discovery/exploration, Survival, friendly aliens
On a lone ship on an espionage/combat/mining/science mission far away from populated space, the detriments of a long mission in a small space begin to wear on the crew. A mix of veterans and greenhorns try to deal with their stress without someone getting hurt, but will they succeed? Or will their vessel be one more on the list of unexplained disappearances?
Themes; Stress/Hardship, Forced Creativity, Strong Emotions, complicated interrelations
The Regulus system is one of the most populous in Earth Alliance space. With six populated worlds and almost a dozen moons & stations, it's a center for trade, travel, tourism, industry, and a number of less savory activities. Terminus Station is the checkpoint that maintains the local warp gate, monitoring all comings and goings from the system. Tractor beams and defense systems prevent shenanigans (or are supposed to), allowing Customs to keep an eye on the shady activities in the system. It also means the station sees the most strange activity in the system.
Themes; Exotic Travelers, Criminal Underworld, Possibly an Oppressive Government, Cosmopolitan Location
Also flexible, strengths include; Magic/Mysticism, Mythic races & Creatures
Some possible ideas include;
The City of Gershom, in the mountains overlooking the coast of the Sapphire Sea, sees more airship travel than any port in the known world. Trade in Dwarven goods from Undermountain, Human goods from the Coast, and other nations reachable by sea or by air come through the cities marble terraces along with strange magics and stranger creatures. All are welcome in the city of Gershom - but not all are treated equal. Racism isn't a cultural norm here, because there is no cultural norm in a city this mixed. But prejudice is as common as any other vice, and virtues are rare here and carefully hidden.
Themes; Slavery, Opportunism, Hope
The Castle of the Emerald Drake is home to the noble Verdanna family, who have ruled the lands around in peace for centuries. The noble and temperate leaders of the family seek to give every citizen an opportunity to pursue their life's dream. Green forests, golden fields, blue lakes and purple mountains are inhabited by a happy people who rarely have cause to worry.
Ruric is a small town a few miles south of the Castle. It is a common gathering point for young people who have not yet decided what to do with their lives. All the guilds have small chapterhouses there, and nobody stays long, save the permanent residents whose purpose is serving the transients.
Themes; Exploration, Idleness, Fantastic Professions
This genre is less interesting to me. Many people find it easier to relate too, though. And it can include both modern & historical settings. Some possible concepts;
Modern communities can include Neighborhoods, Universities, large companies, entire small towns, etc.
Historical Setting could include; World War II, The Wild West (or the same era in the east, or Europe - these are quite interesting periods), the Renaissance, the Napoleonic or Hundred Years' Wars, and more.
Here's another twist; Alternate History. There's a wealth of material regarding this subject available to roleplayers, with many kinds of what-ifs. Though often relegated to Science Fiction, that label only applies (IMO) if travel between histories/times exists. What if you just assume that this was always the history of this setting? (I have some links I can send, if you want more on this one)
So, that's my thoughts on the many options. I enjoyed working out a few concepts, even if just as a creative exercise, so thanks for the opportunity! (Even though it's not quite what you asked for:) ). In the end, I chose Science Fiction, because I recently read Mirrors: Infinite Macabre, from White Wolf. The setting crosses space opera with horror, and if you take out the references to most of WW's game lines (W:tF, V:rR, M:tA, and a few others), it's a pretty interesting setting. I'd love to see a game that centers on a station/planet/system and the ships that move through it. At least once in my life, I want to play a scene involving the interstellar travel from that book. Chillingly intriguing.