It depends on the genre they're into, but one thing's for sure: I wouldn't start anyone w/ The Last of Us. I've been playing games for almost 25 years now, and at times that game still packs a hefty challenge for
me.
Assuming we're excluding Nintendo Games and anything released before this generation (and I'm limiting this to 1 game per genre)...
1st Person Shooters - Bioshock: Combat can be challenging, but there's no real penalty for death under the default settings. There's also a strong emphasis on storytelling and atmosphere.
3rd Person Shooters - Tomb Raider: The most recent game - it's as polished as Uncharted, but with better combat and some really impressive set pieces. Combat is also less punishing than Uncharted is on average, and you have more options.
RPGs - Valkyria Chronicles: The game has something of a stiff challenge, but it's one of the most inventive games in the genre, not to mention prettiest. It's a game that's easy to grasp with a good story, but with deep mechanics and strategy. And yes, it is an RPG AND a Strategy game.
Racing - Split/Second: This is a seriously good arcade racing game, but at its heart it has many similarities to the Mario Kart franchise with its rubber band AI and tracks that can change at any moment. The rules are easy to understand, but the mechanics are difficult to master. And dropping a jet liner on the 7 cars ahead of you is just too cool NOT to see.
Music - Child of Eden: Yes, Child of Eden. For all its pretense at being this casual rail shooter light show, Child of Eden doesn't pull its punches. If you don't get the hang of how it plays very quickly, it WILL kick your ass. That said, the music and presentation is absolutely phenomenal.
Stealth - Mark of the Ninja: Once again, the rules are easy to understand, but the game packs a hefty challenge. But anything you might
want to do in a given situation, the game not only
allows you to do but
rewards you for doing it. Splinter Cell: Conviction's another excellent choice there for similar reasons.
Platformer - Hmm...I would give this one to Ratchet & Clank: A Crack in Time, despite generally liking Sly Cooper: Thieves in Time better. The storytelling is very good, the game does an excellent job of catching you up on the overall story, and there are some truly devious time puzzles in the game. Plus, weapons. Lots and
lots of cool weapons. Its overall style would definitely appeal to someone weaned on Nintendo titles. If they like their platforming on the ridiculously fast and hard side, it's hard not to argue for Super Meat Boy.
Adventure (Zelda-style games) - Darksiders: An obvious pick, but the 1st Darksiders pays such homage to the Zelda franchise it's pretty much impossible not to recommend it as a 1st entry in the genre to someone used to Nintendo titles.
Adventure (P&C-style games) - The Walking Dead: Season 1: Another obvious pick, but I really can't think of a better introduction to the genre for a modern player.
Survival Horror - Dead Space: While Dead Space 2 is a better game IMO, Dead Space 1 better introduces players to the game's concepts.