Current US 21/221 from NC to Independence except at the New River it used Grandview Ln and Old River Ln (SR 700/701).
North of Independence, US 21 followed some abandoned alignments; SR 825 at Longs Gap; SR 614 at Elk Creek; In Wythe County US 21 used abandoned alignments west of current US 21 then the lengthy (and now discontinuous) SR 684 through Speedwell and Stroupes Store before dancing with present US 21 one more time south of Wytheville.
In Wytheville, US 21 used Railroad Ave to 18th St north to Main over to Tazewell St back to current US 21 which becomes US 52 at I-81. US 21 used US 52 to Bland CH except Green Acres Dr/loops at/near SR 656; several abandoned loops out to SR 680; SR 659 Kegley Dr west of I-77.
US 21 followed US 52 from Bland CH to SR 612 then abandoned east of I-77 that winds more than a mile. US 21 picked up again on SR 648 back to US 52 at Bastian. US 21 followed US 52 to South Gap except for SR 642 through Hicksville. US 21 then followed I-77 north's right-of-way until it curves nW to the VA 61 interchange. US 21 picked up SR 685 to Rocky Gap where it used the SR 628 loop, then US 52 north to VA 598. VA 26 followed VA 598 halfway up the mountain, the switched back northeast on what is now abandoned routing to the West Virginia line in the vicinity of the I-77/US 52 tunnel.

US 21 comes to Virginia 1926 Official

US 21 northeast into West Virginia 1932 Bland County

Adjustments:About 1932, US 21 was removed from SR 628 in Rocky Gap and placed on current US 52.
In July 1933, VA 26 was dropped from US 21.
In October 1934, US 52 was added to US 21 from Wytheville north to West Virginia.
About 1935, US 21 was totally rebuilt south of Wytheville, leaving behind a lengthy SR 684 (some since abandoned) and other abandoned alignments south of Speedwell.

US 21 original routing south of Wytheville 1932 Wythe County

US 21 rebuilt south of Wytheville 1936 Wythe County

I believe US 21 was removed from SR 642 Hicksville in the mid-1930s.
In March 1937 (CTB), US 21 was rebuilt in the Elk Creek area, leaving behind abandoned alignments plus a piece of SR 614.

US 21 original Elk Creek routing 1932 Grayson County

US 21 rebuilt around Elk Creek 1958 Grayson County

Also in March 1937 (CTB), US 21 was given a different Wytheville routing by following Main St further southwest with US 11, then replacing some of VA 89 as Main bends south on 24th St then south to connect with the original route at Railroad Ave.

US 21 original Wytheville routing 1936 Wythe County

US 21 modern Wytheville routing 1958 Wythe County

In Oct 1951 (CTB), US 21 was placed on new alignments north of Wytheville leaving behind a number of abandoned segments.
In Aug 1952 (CTB), US 21 was placed on one-way alignments north of US 11 in Wytheville. NB used Tazewell St to Monroe St to 4th St while SB used 4th St.
In Aug 1960 (CTB), the Wytheville mileage reimburesment was changed to have US 21 use 4th St south to the one-way splits instead of Tazewell St. However, the 1958 Wythe County atlas already showed Tazewell St as SR 735. Given that VA 90 was downgraded to SR 749 in Dec 1953 (CTB), it is possible the relocation to 4th St actually occurred in the Aug 1952 action.
In Feb 1971 (CTB), US 21 was removed from SR 659 Kegley Dr west of Bland CH.
About 1975, US 21 was placed on US 52's current routing from Bland SR 612 to Bastian leaving behind abandoned routing east of I-77 plus a little SR 648. Also, US 21 was placed on US 52's current routing from South Gap to VA 61 then over to Rocky Gap, leaving behind I-77's NB lanes and some SR 685.
In June 1979 (AASHO), US 21 was truncated to I-81/US 52 in Wytheville, leaving behind US 52.

US 21 before I-77 alterations 1974 Official

US 21 after I-77 alterations 1975 Official

US 21 removed from US 52 1980 Official

I cannot find any reference to when US 21 stopped using one-way alignments in central Wytheville but from personal experience it was before 1987.
In Oct 1990 (CTB), US 21 was rebuilt from the NC Line across the New River, leaving behind parts of SR 700 and 701.
Improvements:  Upon designation in 1926, US 21 was fully paved only a few miles north out of Wytheville.
In 1930, US 21 was paved from the Wythe/Bland line to Bland CH.
In 1932, US 21 was paved from North Carolina to Independence and from Wytheville to West Virginia.
In 1936, US 21 was paved in the Elk Creek area.
In 1937, US 21 was finally fully paved.
US 21 was multilaned on its VA 61 multiplex at I-77 in 1975.
US 21 is multilaned on Main St and 4th St in Wytheville back to at least 1987 and probably earlier.
Posted:  Fully posted
The only known US 21 cutouts remaining are at SR 805 (old VA 95) approaching US 21 in the Elk Creek area. Independence cutouts were still up as late as 1993.
There was a VA 21 error shield NB leaving US 58-221 in Independence in 2007 and a VA 21 error shield SB in Elk Creek in 2000. Both have been corrected.
Multiplexes:  US 221 (3.86 mi)
US 11 (0.31 mi)
Legislative names: R.A. Doughton Memorial Bridge over the New River (2-18-38); Reverend J.W. Rader Memorial Bridge over Elk Creek (3-5-40)
Other names:  New River Pkwy (S. of Independence); Elk Creek Pkwy (Grayson Co. n of Independence); Grayson Tpk (Wythe Co); Grayson St/Main St/4th St (Wytheville).
Scenic Byway:  No segments
Comments: The 1981 official erroneously shows US 21 with US 52 north of Wytheville.
Although it is not designated officially as a scenic byway, I think US 21 is a pretty ride in Virginia.
I believe US 21 is the only US route with three daughters (221, 321, 421) that are longer than the parent.