All depends on what you like. Multiplayer wise, I enjoy having a few friends/family over and having a crack on Warioware, Mario Strikers and Boom Blocks.
If you're online then Tetris Party is worth a download for multiplayer and World of Goo is well worth downloading if you like puzzle type games.
They're old but two of my favourite games on the system are Excite Truck (graphics are poor but the gameplay is fun) and Ghost Squad which I prefer to House of the Dead Overkill.
Other than that, most of the above recommendations are pretty much spot on.