In my own homebrew worlds I've tackeled this in a variety of ways. Some of my more recent methods were:
1. Make them Fey. In a recent campaign I made gnomes fey instead of humanoid. They acted as a go-between, if you will, between the faerie races and the remaining mortal races. Often this role is given to elves, but I felt that it made the gnomes stand out more. While I made few changes to their statistics (this was a 3.0 game not the revised) just changing this one aspect of their race went a long way to making them unique.
2. In a second world I had two races of gnomes. One was akin to the typical race from the PHB, while the other was much more mystical. Statistics wise, they gained Detect Magic (in addition to their other innate spells). I believe their ability score modifiers were also different(can't remember the exact details at the moment, intelligence or wisdom bonus I believe). Where they really differed was the culture. They lived in small tribes that kept themselves isolated and hidden for the most part. Their society was theocratic, where their spirtual leaders also managed many secular matters. I tried to emphasize their reliance on magic in general, which pulled them away from the typical image my players had of tinker gnomes. And this reliance on magic was a larger step away from the very non-magical image my players still have of dwarves.
3. My most recent campaign has the gnomes being a nomadic race that live in a region called the Sinking Forest (forest/swamp) where they are skilled hunters and warriors. In this situation I made Ranger their favored class and in general I try to emphasize some of their combat skills and abilities. Gnomes are a small race which makes them great stealth warriors. Of course it also helps that in this game the primary dwarven group is a barbaric mountain race so the cultural differences are more pronounced.