I'll choose between Mario Strikers or Inazuma because theyre newer and more popular so... *flips coin* Mario Strikers.

Portal (although whether GLADOS is female is debatable)

The second part's throwing me off.

Where on Earth is Carmen Sandiego?

or maybe System Shock 2 or Portal?

I think the second part fits Portal best since it was part of the Orange Box.

It's brilliant to see Portal appear on so many lists... so I hope so

It's Portal 2...I worded the second part poorly.

I would have argued that Sarah Kerrigan is the best female antagonist in a video game but StarCraft II kinda messes things up but if you consider only StarCraft and Brood War, Kerrigan kicks major ass!

My #44 is an RPG based off of a license that had already been around for over two decades at the time of the game's release.

Baldur's Gate? I think it came out 24 years after Dungeons and Dragons.

I'm partial to Icewind Dale, but no matter. None of the great 90s PC RPGs made my final cut anyway, thanks to my heavy Nintendo bias.

#44 XCOM: Enemy Unknown

Well, this was a surprise. I picked up this game during the Steam Summer Sale for $10, then proceeded to play the shit out of it for the following couple weeks. Enemy Unknown is an intelligently designed (albiet somewhat imbalanced) strategy game with pits the player against a mounting alien threat. It manages to make most player decisions rather complicated and stressful, and imbues a strong horror atmosphere into every turn-based battle. It's an entirely engrossing strategy game.