I'm sure there's countless highly popular games that I've never run. Some come to mind that I picked up on GOG recently, since they've been running sales.
Tomb Raider - I remember being skeptical of this game because of the apparent gimmicks of sex appeal + 3D. I'm still skeptical, but given the series' fame all these years later it must have been a decent game. It's iconic of the late 90s 3D revolution, so I want to check it out.
The Wing Commander series - the only one of those I ever played was Academy, which I thought sucked, and I guess the WC fans agree with that. I quickly went back to X-Wing. I need to try the others out. Seems almost any of the other WC games are actually known for being good games, unlike the 'Academy' iteration that gave me such a bad taste.
Tie Fighter - I loved X-Wing, and I like X-Wing Alliance, but I've never seen Tie Fighter at all.
LucasArts and Sierra adventure games - never played any of them.
Up until recently I had never played Unreal (1998) either. I did install and play it about a week ago. I still haven't played Unreal 2.
I've never played Quake 3 or DOOM 3. The most popular benchmarks in the world, apparently.