Mine is completing the Return to Sender quest.
In that quest you have to visit all of the Ranger Outposts in the map.
Finding how to get to Outpost Foxtrot (the 6th and last you have to visit) was a nightmare. I gained 2 full levels due to all the fighting and exploring I did to find it!
It took me about 3 real-time hours and about 4 reloads (due to getting killed by insects!) to get there.
In the process I discovered a vault, a drug dealing lab, 2 factions, a bootlegging beer factory, and not enough goodies!
Whoever designed this section of the map thought it would be funny to make you go around in circles forever.
To that person: "You are not funny."
However, the end reward was worth it.
Depending on your choices, you can end up with the revolver the Fallout: New Vegas cover art has, and it's worth every step of the way (if you use revolvers, like I do).
How about you?
