Hmm, good question; there are so many that stand out.
I think the game that stands out as the best I've ever played is The Legend of Zelda - Twilight Princess. Intended as a GameCube title, it was rearchitectured for the Wii's controllers (which in turn required a right-handed Link to match the control scheme, and that ended up requiring the developers to mirror the entire game). Some will prefer Ocarina of Time, being the first full-3D title in the Zelda series and introducing key gameplay features of the series such as Epona; others prefer the smoother graphics, motion-tracking controls, novel world concept and less linear character progression of Skyward Sword. For me, TwiPrin gets the nod for its gritty, real graphics, rich story with extended NPC roles, and incredibly immersive gameplay, including being the first title to let you actually swing a sword. The game also uses Epona as more than just a mode of transportation and a few mounted mini-game experiences; several set-piece engagements require you to master mounted combat.
Honorable mentions include:
* Half-Life - The game that represented a fundamental shift in the thinking behind the first-person shooter, from the "run-around-and-kill-everything" model that Id Software made its millions on, to the "thinking shooter" that required more skillful gameplay, conserving ammo, using your environment, interacting with NPCs etc. The backstory is brilliant, the in-game story massive, and the arsenal you wield ranges from the iconic (crowbar) to the comical (snarks) to the truly awesome (gluon gun).
* StarCraft - Blizzard's starship-trooper take on their RTS engine, StarCraft is the single most successful title in the genre to date. It was among the first to tie the various factions' campaigns together one after another into a single storyline as opposed to presenting incompatible alternate realities, which was more or less Westwood/EA's model with the Command & Conquer franchise until C&C Generals. The amount of paper-rock-scissors army composition strategy inherent in the gameplay is among the best ever, and the large but limited army size makes for some truly epic battles.
* Legend of Zelda - A Link To The Past - Probably a close third in the Zelda series to TwiPrin and Ocarina, the SNES's canon Zelda title was the first "pick up and go" Zelda game that didn't need an instruction manual to give you the story, and it introduced several key concepts that are ubiquitous now, such as crystal switches, multi-level dungeons (and three-dimensional thinking), Pieces of Heart, and an alterego or henchman character for Ganon.
* Hitman 2: Silent Assassin - I enjoyed the original, Codename 47, which along with Tom Clancy's Splinter Cell truly ushered in the "stealth shooter" genre, but Silent Assassin really established the Hitman series as a force among shooters. Where the original pretty much forced a particular play style, SA merely encourages it; you are free, in any scenario, to simply show up with an M60 (once you have one), kick in the front door and hold down the "fire" button until everything that dares come to investigate the noise is reduced to a pile of bloody rags. Very cathartic after a hard day at work.
* Legend of Zelda - Ocarina of Time - Can you tell I'm a Zelda fanboy yet? I do enjoy this game, being the first full-3D title in the series and all, and the gameplay is a bit more free-form than TwiPrin. It similarly introduced a lot of now-ubiquitous gameplay concepts in addition to the 3D world, such as Epona, power-ups for items besides your sword, things like night and day varying the conditions you experience, etc etc.
* Final Fantasy VII - The most popular, by far, of the Final Fantasy franchise. This title has story to spare, plenty of minigames, an intuitive yet flexible battle/equipment system with the Materia paradigm, which could effectively give any character any spell.
* SimCity 3000 - This one, IMHO, represents the pinnacle of SimCity gameplay. SimCity 2000 was good, especially with the building editor allowing you to tweak your own tileset, but it could be glitchy at times, and if you went into debt you probably weren't getting out. SimCity 4 pushed a good thing too far, going with the creepy Sims-style character animations, requiring you to micromanage every clinic and police kiosk, and basically requiring region play in order to have the most success with any one city. SimCity 3000 kept the basic idea of 2000, but added a bit of whimsy with the cartoon characters, improved graphics, gameplay and editing, and gave you a lot of options (and challenges) for zoning and development, making for a level of simulation that felt manageable while not creepily real.
* Diablo 2 - Blizzard's holy trinity of game universes wouldn't be complete without the Gothic medieval world of Diablo. A stepping stone between the text-only MUD and the life-consuming MMORPG, the Diablo franchise's level-based adventure style gameplay is extremely addictive even if the integration of the storyline is repetitive at times. Diablo II was a natural progression from the original, expanding the story and making the gameplay feel slightly less grinding without losing the hands-on, you-against-a-million feel that made the original so much fun.