Still on my bucket list/dream drives I probably won't take for various reasons:
Drive to Alaska and back, hitting all the municipalities while there.
James Bay up and back
Labrador/Newfoundland round trip
If I ever became insanely wealthy, I'd want to drive every U.S. highway end to end. But, being a realist, one trip I would like to make, maybe once I'm done hitting counties, is to drive the entire length of U.S. 2.
I've been on a big stretches of it, including a fun trip a few years ago from Spokane through Shelby, MT. I'd also like to add U.S. 6 to that across the country as well. Driven on many many stretches of it in my life, including all of PA and most of Ohio.
One other trip I'd like to make some day is if I get out west again without another destination in mind and drive U.S. 50 from at least the CA/NV line to I-15.