There are always a couple games in every generation that become very rare and hard to find. This is usually due to the game being a quality game with a limited quantity release. There are many rare Japanese games also, but today I will be focusing on American releases. Check them out and see if you own any of these rare gems! (Keep in mind that the prices are averages)
Clubhouse Games

Used - $45
Sealed - $65
The Clubhouse Games pack is still worth the used price simply because it has so much to offer. It's basically a giant collection of card, board and parlor games, so most people would have fun with it. I have watched this game slowly rise in price over the years, and it probably isn't going to be stopping here. Get it while you can!
Electroplankton

Used - $60
Sealed - $100
Electroplankton is kind of an experimental music game where the player makes music by interacting with different kinds of plankton. When Electroplankton was first released, it could only be bought from limited quantities online. Especially with the publicity it got in “Super Smash Brothers Brawl”, it's no wonder that this game is worth so much.
Etrian Odyssey

Used - $40
Sealed - $60
Certain Altlus games, like this one, tend to become more valuable over time. It's most likely because they never release that many copies. This dungeon crawler RPG is worth picking up for the gamer and collector alike.
Monopoly 4 in 1 pack

Used - $65
Sealed - $90+
Atari was very quiet about releasing this game back when it came out. I'm sure most people that bought it didn't realize it would be worth so much now. It really isn't the most brilliant game pack out there with some of its lacking features (no single pack?), but it is worth buying for the DS collectors.
LOL: Never Party Alone

New - $20
Think of DS pictochat versions of Apples to Apples or Pictionary and you get this cute game called LOL. As you may have noticed, this game is still very new. There is no doubt it will be valuable some day as it is only being released on Agetec's website. It's basically going down the same route as Electroplankton did, so I'd expect this one to double in value in a couple years. Buy it new while you still can!