U.S. 21
Back in the good old days, US 21 went all the way to Cleveland, OH, before I-77 replaced it.  I don't see any reason why it can't go back there again.

From its current terminus in Wytheville, VA, US 21 would continue up US 52 to Bluefield, WV, then swing onto US 19 through Beckley to Fayetteville, WV.  It would then follow WV 16 to Clay, WV 4 to Ivydale and WV 47 to Parkersburg.

US 21 would then enter Ohio on US 50, and follow OH 7 to Marietta.  Then it would multiplex with I-77 to Strasburg, OH, where it would replace OH 21 as the bypass route of Canton and Akron.  After another I-77 multiplex, it would enter Cleveland on OH 21, and East 71st Street would be upgraded to US 21.  The new US 21 would end in downtown Cleveland on OH 14/Broadway.

This would be a perfect opportunity to bring US 21 back to Cleveland, especially now that US 121/Coalfields Expressway is set to open soon.  US 21 and US 121 would meet in Beckley, justifying the latter route's existence.