Going to need more to go on. The kinds of games people like really are a personal thing. I like nice developed RPGs (role playing games) with a good deep story, and have little patients for fighting games or beat-em ups. Other people love those kinds of games, and hate the time and effort it takes to get into a good RPG.
One of the better genre crossing games might be Metroid Prime. It does a pretty good job of mixing sci-fi, action adventure, and shooters with a respectable story and some other RPG elements. You play the part of a space bounty hunter who has this highly advanced battle suit that helps her traverse varied terrain, fend off indigenous life forms to different planets, etc. Almost every game starts with you crashing on some planet, losing most of your suits gear, and having to collect it all again as you try and find your mark. There's Metroid Prime Hunters for the Nintendo DS, the only problem is, it's probably only a 20-30 hour game... Which is huge for a handheld game, but if we're talking a multi-day bus ride...
So I might also suggest something like Worms: Open Warfare. Kind of a cult classic, it's a 2D strategy game, where you have a team of little cartoon worms, and you're trying to obliterate the other team of little animated worms using all kinds of amusing weapons, like sheep bombs, holy hand grenades, etc. The worms will usually have amusing comments to make after every turn. You can get this for both the Sony PSP and Nintendo DS.
It's also pretty hard to go wrong with any of Nintendo's Zelda titles. If he like movies such as Lord of the Rings, he'll probably love Zelda. Basically a lone kid wearing green clothes who has to set out to stop some evil villain who kidnapped the princess or is somehow threatening the world. Armed usually only with a simple sword and shield, you have to traverse many dungeons, fight many enemies, and collect different items to help you along your way.
Then there's more traditional role playing games like the Final Fantasy series. They can be a bit of an acquired taste. You can get Final Fantasy 1-6 (except 3), and Final Fantasy Tactics for the Nintendo GameBoy Advance, which the Nintendo DS can also play. Final Fantasy 3 is a Nintendo DS only game. Final Fantasy Tactics is a tactical RPG, and most people either love or hate these kinds of games. They're very slow and methodical, requiring a fair bit of planning for every move. But the usual formula for a Final Fantasy game is that the world is in some sort of peril, and a ragtag group of people end up being the only ones who can stop it.
I think there's also the first two parts of the Xenosaga trilogy out for the Nintendo DS. While most of the voiced over cut scenes from the PlayStation 2 originals were likely removed and replaced with text, this series of games is a rather interesting sort of sci-fi space opera. Set in the 6000s, strange beings known as the Gnosis have been rampaging across the universe... The sort of last hope for the human race is a battle android named KOS-MOS. There are a number of twists and turns along the way, and they actually weave a lot of judeo-christian mythology into the plot.
I'm mostly an RPG person myself, so that's where my mind goes when thinking up games. I know it's supposed to be a gift, but maybe you should try asking him what sort of games he liked playing as a kid... Or take him to Target or Best Buy with you and have him pick out a couple of games that seem interesting, and just buy them for him. Well, have him pick them out, then use a game review site like IGN and Gamespot to see if their reviews are favorable. If the game doesn't get over a 7.0 score, it's probably not worth buying in my experience, but they should also have links to similar games to the one you were looking at, and you can probably find a couple of good ones.