No particular order:
New Super Mario Bros (DS) - Now I'm not an advocate of using sales to measure the accolades of a game, but if I'm not mistaken this was the best-selling standalone game of the generation, and for good reason: It caused a huge resurgence in 2D gaming overall, even causing indie developers to play a much bigger part in mainstream gaming in over a decade, making the rise of 3D worlds in the previous two generations look fad-ish at best.
Street Fighter IV - Without it, NRS and a lot of other developers would never have been inclined to return to their 2D roots, and showed that the 2D fighting genre is still very viable today and helped the competitive FGC become bigger than it's ever been.
Gears 1 - Very explicit outlook on the 3rd person shooter genre, perhaps benefited too much from it's own surprise breakout, because Gears 2 went downhill tenfold.
Metal Gear Solid 4 - Hideo Kojima was constantly scrutinized for developing the game on a platform that was pretty much public enemy #1 at the time (PS3), but stuck with it to achieve his visions and dreams, and provided a magnificent conclusion to the mainline MGS series, thus helping the PS3 truly take off.
Mortal Kombat 9 - Despite being progressively unrealized by a development team who probably has the worst NDA management in the industry's history ("the price of divekicks", anyone?), it brought together a community that was able to break the stalemate of non-Capcom games being able to make 3 consecutive appearances at EVO, coming from a franchise that was quite possibly on it's deathbed 4 years ago. Would I put up with another character that got stiffed on frame data to live through it all again? Damn fucking straight.
FIFA 10 - I admit, I was a huge PES fanboy during the PS2-era and used to trash talk FIFA relentlessly, but from here EA have definitely picked up on Konami's slack and helped football interest grow in regions who don't normally give a shit about it.
Killzone 2 - the first time I was actually impressed by the technical boundaries of a console game since MGS2, had a really gritty and realistic feel to it and provided very well rounded online. But like Gears 2, Killzone 3 didn't really know what it wanted to be, half-assedly cashing in on the COD crowd, and since they still didn't care, it sadly became a clusterfuck quick.
Little Big Planet 1 - I'm not trolling here. And to be honest, it's not even my favorite platformer of the generation. But IMHO it showed everything that online communities should be about, and I hope that continues next gen.
Pokemon Black (or White) - I tried my hardest to get into the previous generation of Pokemon games and it just wasn't happening, maybe it was too similar to the GBA games? But I never stopped being intrigued by the risks and technical effects Game Freak did here, especially with draw distances, animations and textures I didn't even think the DS was capable of, it felt great to have an entirely new, unknown roster to work with too.
Call of Duty 4 - Stepped into uncharted waters by focusing on recent eventsand their repercussion in the middle east, and was actually the last COD game that won people over by.. *gasp*.. having a great campaign. Then all the overly-entitled frauds came waltzing in, and, well, I think we all know what happened to the series after that.
