Age of Empires 1 , 2 and 3. It's the basics of RTS!

Star Wars: Knights of the Old Republic.

There are some other games, but some of those are unlikely to make it here in the nearest future or at all (Dishonored, Skyrim, Half-Life, the new X-COM... now that I think of it, the old one as well, Devil May Cry 3-4... too many of those).

Oh god, this is torture... Only 1, eh? I'll go with SWAT 4 for coop awesomeness but any of these would also make me happy:

NOLF series
Mech Commander series
Freelancer
Star Trek Bridge Commander
AVP 2

Battlefield 1942 including it's expansions Road to Rome and Secret Weapons of WW2. I was so disappointed when Origin had a free version but without the expansions and then it got removed completely. For mp-fans GOG Galaxy could do the matchmaking now that GameSpy is no is more.

These games are must have on gog in my opinion (sorted alphabetically):
Blade Runner
Call Of Cthulhu: Shadow Of The Comet
Captain Claw
Chasm: The Rift (A.K.A. Chasm: The Shadow Zone)
Crime Cities
Dark Colony
Dark Earth
Dethkarz
Drakan: Order Of The Flame
Earthsiege 2
Emperor of the Fading Suns
Fantasy General
Hardwar
Heavy Gear II
Myth II: Soulblighter
Myth: The Fallen Lords
Oni
Outlaws
PowerSlave (aka Exhumed)
Requiem: Avenging Angel
Revenant
ShadowCaster
Star Wars: Dark Forces
Star Wars: Jedi Knight: Dark Forces II (with CD AUDIO music)
Star Wars: Jedi Knight: Mysteries of the Sith (with CD AUDIO music)
Star Wars: Shadows of the Empire
Star Wars: Tie Fighter Collector's CD-ROM (DOS version)
Star Wars: X-Wing Alliance
Star Wars: X-Wing Collector's CD-ROM (DOS version)
System Shock
Take No Prisoners
Terra Nova: Strike Force Centauri
Warhammer: Dark Omen
Warhammer: Shadow of the Horned Rat
Warlords III: Darklords Rising

Would be cool to have on gog:
Black Dahlia
Call Of Cthulhu: Dark Corners Of The Earth
Civilization 3 GOTY
Civilization II: Test of Time
Command & Conquer: Red Alert 2
Command & Conquer: Red Alert 2 - Yuri's Revenge
Doom 1 & 2
Emperor: Battle for Dune
Evil Islands: Curse of the Lost Soul
Fable (1996 adventure game)
Freedom Fighters
Get Medieval
Heart Of Darkness
Heavy Metal: F.A.K.K.2
Heretic: Shadow of the Serpent Riders
Hexen + Deathkings of the Dark Citadel
Hexen II + Portal of Praevus
Kiss Psycho Circus The Nightmare Child
Max Payne 1 & 2
No One Lives Forever 1 & 2
Quake 1 & 2 with all expansions and CD AUDIO music
Rage of Mages
Rage of Mages 2: Necromancer
Red Faction
Rising Lands
SimCity 3000
Soldier Of Fortune 1 & 2
Spellcross: The Last Battle
Star Trek: Elite Force 2
Star Trek: Voyager Elite Force
Submarine TITANS
Touché: The Adventures of the Fifth Musketeer
Tron 2.0
Vampire The Masquerade: Bloodlines
Warhammer 40,000: Chaos Gate
Warhammer 40,000: Rites of War
X-Com 1 & 2
X-COM: Apocalypse

For me? Hm, I'm sure it's expected of me to say Vampire The Masquerade: Bloodlines (which I just did) but I'm actually going to say The Neverhood. I'll be selfish and say that I already have Vampire The Masquerade: Bloodlines in DRM-free form, and while I would definitely buy it again if it came to GOG (due to a lack of confidence in Gamestop, to be honest) I would rather have The Neverhood here since I've never played it but I'm a huge fan of its sequel Skullmonkeys.

#1 Vampire: The Masquerade - Bloodlines

The one game... hmm... currently it would be a close one between Skyrim & FO:New Vegas.... To choose one I'd go for Skyrim first.

Now that you made me thing about it again OP I expect you to make it appear in the gog store by tomorrow :P

If it has to be only one game, I want to see Day of the Tentacle here!

Lode Runner, either the original or the Sierra remake...or both!

Where can Vampire The Masquerade:Bloodlines be had DRM-free?

It used to be DRM-free on DotEmu before Activision decided not to renew their contract there. Seeing as Activision seemingly never lowers their prices I don't know if we'll eventually see it show up here for $20 or not.

blade runner from westwood!

You could go for a physical copy. New it is quite expensive but second hand you can get the game for about 3-4€ in Germany.