Now I never said it would make a great main storyline. But it would be interesting as a sub plot.
Let's say on your way to the main plot you happen up on the ant lair and if you eliminate their hive then they stop appearing in the wasteland. The choice would be yours and of course you'd gain some nifty... something from doing this.
I suppose I could try and come up with a real plot of some sort.
Okay let's take an average Fallouty person. Ah. A ghoul. There's your villain. Okay ghouls live a loooong time right? See. This ghoul's a Nazi (humor me). Okay this isn't known at the beginning of the game of course. He's in power armor and he's actually part of the Brotherhood of Steel. Head of a large faction of it as a matter of fact. Guess what? You're one of his soldiers. Throughout the game you're given orders to go kill out various mutants and such because this particular ghoul despises even other ghouls, super mutants, deathclaws, every type of abnormal and of course he loathes the wasteland fanatics as well.
But you don't know this and you're frequently given orders to go take out various factions under the notion that they're "bad" people. Okay about halfway through the game you find out this is NOT the case and you get to investigate. You find out the truth. Now you have the option to go up against the Brotherhood, turning on your own comrades just to get at the evil within it, or you can attempt to assassinate him (which would likely result in your own death) or expose him or whatever. You're the only one that knows he's a bloodthirsty Nazi ghoul and.. well there's your plot. Happy now?
You can work my ants idea into this as well. If you expose him he retreats to a hidden bunker and the ant hive happens to be in the way. Oh and he is a Nazi scientist so the later half of the game once he's exposed you spend that time fighting his cyborg creations. Maybe the old bunker he retreats to has a secret lab of his he's been working on for a while?
Well anyway that's not an overdone plot (except for maybe the undead Nazi bit) and there's even a plot twist. The "want to destroy your own kind" bit has been done though in (spoiler) Stranger's Wrath, but without explanation in that instance.
Edit:
You could make the game even longer by not starting out as a Brotherhood soldier. You could work your way up to becoming one. Maybe start out as a villager or maybe even a raider. Heh. There's a good one. The game starts out with you as a raider and you get to do what you want for a while but when you come back to your home base later you find the Brotherhood there and while you do put up a valiant fight they defeat and capture you and try you out in their reform program.... or something. I know. The BOS usually don't take raiders as prisoners but it would be good for the plotline if you decide you want to be evil later on. Heh.
"For God so loved the world, that he gave his only begotten Son, that whosoever believeth in him should not perish, but have everlasting life. " -John 3:16
Hopes. Dreams. You have to live these things. If not, they will remain prisoner within the confines of your mind for the rest of your life.