For the most part, the True20 system is streamlined and fairly ergonomic. As it stands, it would be fairly easy to run a generic Medieval game, a modern game, or even a hard Sci-Fi game right out of the box (so to speak). There are, however, a number of situations where you’d need a fair amount of work.
The most noticeable setting problem I see is for those hoping to use it for a AD&D style game world. The game has plenty of skill, feat, and gear options to create a perfect character for this setting, but the problem comes with the magic system.
Since True20 is designed to fit any campaign style or setting, they handle magic, psionics, and any other kind of wild talent with the umbrella ability of Powers. If you were running a magic rich fantasy setting, this is your basic group of spells. And even though the book includes a fairly large number of Powers, not all of them would be appropriate for a magic setting (some are obviously better suited for Super-Powers or psionics than magic), and those that are appropriate don’t always come together to make a great mage.
For that reason, I can’t help but wonder if this will be addressed in the True20 Companion in some way. If not, it seems like a tradition AD&D style setting would take an enormous amount of work on the part of the Narrator.
Conversely, a hard Sci-Fi setting is easy to create with the True20 setting, with the exception of equipment. While it would be rather easy to build characters, define the scope of the game, and even drop in a psionic system (if you wanted one), the usual range of gear that so many Sci-Fi buffs adore would require a fair amount of work on the Narrator’s part.
I will say that creating races (either Sci-Fi or Fantasy) is easy. In fact, the same goes for monsters, as True20 gives you a “creature template” for a huge variety of critters, making it a snap to throw together a new fiend.