Great NSX Drives - Southeast US
Drive 1 - U.S. 250 from Virginia to West Virginia
U.S. 250 from Staunton VA, going northwest over the mountains into WV. Excellent road for sports cars or motorcycles. Two lanes on the big uphill stretches for passing.
Drive 2 - Skyline Drive (VA) and the Blue Ridge Parkway (VA and NC)
There aren't a lot of directions involved - you just get on Skyline Drive and/or the Blue Ridge Parkway (BRP) and drive - so instead I'll try to highlight some fun stops and things to see along the way and provide some tips.
Skyline Drive runs the length of Shenandoah National Park, It is $10/vehicle to enter and total distance is somewhere around 130 miles, but it is easy to spend the entire day traveling it if you stop to see some of the things along the way. It begins just off I-66 near Front Royal, VA. Take Exit 6 off I-66 to Front Royal and follow U.S. 340 South until you see signs for Skyline Drive.
Lurray Caverns is near the north end of SD, and is pretty neat. They also have an automotive museum if you are interested in that sort of thing, and admission is included with a tour of the caverns. Take a look at their web site at ">www.luraycaverns.com for more information.
Skyline Drive ends right at exit 99 on I-66. Very conveniently, the end of Skyline Drive is the beginning of the Blue Ridge Parkway!
The Blue Ridge Parkway is flat out one of the best driving roads in the entire country. Unlike Skyline Drive, the parkway is free. In my opinion it is a much better driving road as well as being about three times longer. It begins right off exit 99 on I-66 in Virginia, which is near the top of Afton Mountain.
Tip: If you go on a nice weekend during peak spring or fall scenery (late April to early June and late September to early November), expect it to be crowded. The exact dates vary depending on how far north or south and the elevation. During these peak time, entire parkway fills up with people driving 30 MPH and regularly pulling in/out of the scenic view areas, so don't even plan on driving fast - just enjoy the scenery. The Parkway is always more crowded on weekends than weekdays. During the winter it is mostly empty because it's not very scenic with all the grasses, bushes, flowers and trees turned brown.
There's web site you might find interesting at  with lots of travel info on it. Getting around the site to find what you want can take a little getting used to, but there is a lot of good stuff there once you get the hang of it. Also, be SURE to check out the GORP (Great Outdoor Recreation Pages) site. If you go to the section on Virginia, it has mile-by-mile maps of the Parkway and a very comprehensive listing of all the stops along the way with a brief description. For the BRP and Skyline Drive stuff, go to the following: 
A trip to Thomas Jefferson's home - Monticello - would fit in nicely between Skyline Drive and the Parkway since Charlottesville is just about 20 miles west on I-64 from where SD and the BRP meet.  This is an interesting place to visit, and Jefferson was big on horticulture so there are some pretty neat gardens.
Places to stay? If you are a camper, there is camping all along Skyline Drive and the Parkway. It's very inexpensive. There is a hotel right at the beginning of the BRP. I have not stayed there personally, but it looks like if you get a "room with a view" you would have some great scenery out your window! There are Inns and Bed & Breakfasts all along the Parkway.
As far as eating.. there are restaurants at several of the stops (Peaks of Otter, Biltmore, etc.), but if the weather is nice you might also consider picnicking. All along both Skyline Drive and the BRP there are some very nice picnic areas to stop at. You are allowed to pull off the side of the road anywhere it is clear and you feel it is safe to do so. So if you see a nice tree you'd like to sit under and have a snack, go for it.
Driving down the Parkway you'll frequently want to pull over and enjoy the view and/or take some pictures. Where the BRP starts at exit 99 on I-64, so that is Mile 1. I'll try and list some interesting stops as you drive down along with their approximate mile marker, but keep in mind that there are many, many places to stop beyond these more "major" ones I'm discussing.
Mile 40 (rough guess) - Get off the Parkway and drive about 20 minutes to Natural Bridge. If you look on a map, you want to get off the BRP on 130 west and Natural Bridge is right by where that connects with I-81. Nice scenery with some easy walking. Wax museum, caverns, some other stuff. Web site at 
Mile 86 - The Peaks of Otter. A large campground and lodge facility with a southern restaurant (most people get the buffet for about $10). Nothing fancy. You can spend the night here too, but I would suggest making a reservation in advance, especially during peak seasons. It's a pretty rustic "get away from it all" atmosphere - last time I checked, they don't even have phones in the rooms. Beautiful lake right out back, and it's worth your time to either hike up or take the shuttle bus to the top of the Peaks. There's an historic farm and some "nature trails" to explore as well.. most are half a mile to a couple miles of pretty easy walking. Search  for "Peaks of Otter"
Mile 120 - Roanoke. This is the largest city in this part of the state, population in the mid-100k range. A trip up Mill Mountain at night provides a great view of the "Star City". If you want to spend a night in a very nice and historic hotel with a great restaurant, make a reservation at the Hotel Roanoke. 
Mile 172.5 - Ch�teau Morrisette Winery and Restaurant - This is an UNMARKED EXIT since it is not part of the Parkway system. Exit right on Black Ridge Road (if traveling south; exit left is traveling north) and make an immediate left onto Winery Road. Just a couple hundred yards and Chateau Morrisette will be on the right. They have some decent wine (esp. some of their Reserve stuff) and a very good restaurant. You really need reservations at the restaurant during the peak spring/fall seasons. They have tours and tasting every day and various festivals, jazz and blues bands, and other special events throughout the year - see the website for schedules. I highly recommend this as a meal stop for either lunch or dinner. 
Mile 176 - Mabry Mill. Restored grist/sawmill, and woodworking/blacksmith shop with people demonstrating period work techniques. Gorgeous setting - one of the most widely photographed and painted spots on the Parkway. More info on the  site (search for the word "Mabry")
The web site  has a lot of good info on the section of the BRP that travels through North Carolina.
Mile 316 - Linville Gorge/Falls. Very pretty, a couple miles of moderate hiking to see some of the more impressive sights. More info on 
Mile 355 - Mt. Mitchell is the tallest mountain east of the Mississippi. Bring a light jacket; it can be a bit cool even in June, especially if it's cloudy.
Mile 389(?) - Biltmore Estate. Largest home in America, built by the Vanderbilts. Your wife will probably enjoy the gardens on the estate's grounds. You can easily spend at least a full day here, and it's not hard to spend two. I recommend doing any "special" events they have when you're there - usually in the evenings. They run "behind the scenes" tours, summer music or wine festivals, etc. These are usually lots of fun. Their web site at  has more info and a schedule of these special events. There's lots of nice Bed & Breakfast places nearby or you can stay at the Biltmore Inn.
Further down there's the Pisgah National Forest and Mount Pisgah, the Black Mountains, etc. I'm not sure how long you're looking to spend on this trip, but you could easily spend 5 days just doing what I noted above if you take your time and explore things.
One final suggestion. Be careful when you're driving, for a few reasons. First, lots of people stop in weird places along the road to take in the view, and their kids may be running around. The road also takes some pretty sharp turns when you're really into the mountains. And, running through the middle of the woods, there is wildlife - at night it is very common to see deer right on or very near the road. It would really put a damper on your vacation to total a car by hitting a deer (and the deer probably wouldn't be to happy, either!) Finally, this is all National Park land. That means it is under federal control. The speed limit on Skyline Drive is 35, and 45 on the Parkway. Speed enforcement can be fairly heavy during the peak seasons. They run enforcement in everything from marked cruisers to "undercover" in trucks or something you would not normally recognize as a law enforcement vehicle. If you get a ticket from them, it's not just the local judge you're talking to, it's a in a federal court.
Sorry this is so long.. I hope it's helpful. If you have any questions or if I can help somehow please let me know. I think this is a great part of the country and am sure you and your wife will enjoy your vacation!