Fastest is 401 to Detroit and 75 south. Boring but quick. More fun is QE to Buffalo and 219 south through all the twisty stuff to Skyline Drive at the top of the parkway. Then ride the Blue Ridge top to bottom and on to the Dragon from Cherokee. First route could be doable in one long day. Second route is probably not possible even in 2 days. Too many nice bits that make you turn around and do them again.
You'll have to decide if you want to get there quickly or take the fun route.
There are also good roads that runs parallel to 75. Any route will be good as long as you avoid the Interstate. I can give you a route that takes 3 days to fully enjoy, depends on what your looking for. But as mentioned above 219, skyline, BRP will be the best one for your first ride down.
I'm a big fan of Skyline/BRP. 219 is ok, but lately I'll just hop on the interstate to Front Royal and save myself a few minutes and a few ticket scares.
If you have the time, The Snake between Bristol and Mountain City, TN is a really nice road. Well worth the detour.
How long can you ride for each day? That makes a big difference. If you can ride more than 10 hours each day for your first two days, there are so many possibilities. That said, here's a sample 2 day route to get there with each day being about 10 hours.
Day 1: http://goo.gl/maps/JDsQK The first day is all slab, so that you can have an awesome 2nd day of riding and stops you in Tazewell, Va where you can find a motel or camp just a bit further at Hungry Mother State Park. There is a toll hwy section shortly after you cross the border and I think it costs around $3US, but saves a bunch of time. Have your change handy if you go this route.
Day 2: http://goo.gl/maps/AiNHw Then the next day, you can ride for a short bit to get your tires warmed up and ride VA#16 "The Back of the Dragon" to prime you for the rest of the day which includes US421 The Snake, the twistier, southern half of The Blue Ridge Parkway, NC226A The "Diamondback", NC80 "The Devils Whip" and more. This finishes up at Iron Horse Motorcycle Lodge.
Day 2 Alternate: http://goo.gl/maps/vEiK8 While I really like Skyline Drive and the Blue Ridge Parkway, I prefer to ride it heading home, so the sun isn't in my eyes. Taking the Blue Ridge Parkway out, this route also give you the chance to ride the NC276/NC215 combo and the NC281 which is a piece of engineering awesomeness.
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