We normally head to the south-east of the US via Erie, PA and down I-79 and US19 to Beckley, WV and then connect with I-77 south. I love driving through the Appalachians from Beckley to the Virginia/NC border. Great vistas and the roads are in good shape. I have no problem with the tunnels and the downhill slopes are not the worst we have experienced. They are relatively easy to drive, IMO, in good weather.
We keep an eye on the weather before we leave Toronto and are prepared to adjust our leaving date, or to sit tight en route if necessary, if the weather will be unusually bad. Most of the time we have been lucky and the weather has been fine. One time we ran into a sudden blizzard as we hit US19 and it was bad, with blowing snow and poor visibility all the way to Beckley, where we decided to stop for the night.
We have also done the Beartooth Pass on our way from Yellowstone to Billings, MT. It was in August, in temperatures of 110 F, so no snow issues. Glad we did it from west to east. Going up the multiple hairpin turns on the way up was fun, but taxed the AC in the car. Glad I wasn't doing it in one of the RVs we passed! The downhill segment was steep and continuous, but good wide highway. It did tax the brakes, though! The route and scenery are amazing, but it took much longer than we predicted (pre-Google Maps days)! Glad we did it.