We definitely have some places we consider must stops, and we may just be guilty of planning routes way out of our way just to be able to eat at them.
In no particular order:
At Sara's Table in Duluth, MN. This is a popular place, and over the last decade or so we have eaten here 9-10 times. Part of it is the ambiance of sitting on the deck when the weather is nice, a large part of it is the made from scratch farm to table type food, and another good part has always been the service. Breakfast or lunch, we've never had anything bad. And we have purchased a few things to take with us (some cranberry bread for my wife, and pure maple syrup infused with something that makes it the best I've had).
Beau Jo's pizza, at least the original in Idaho Springs, Colorado. Fresh made dough daily using honey as the sweetener, fresh copious ingredients, and honey on the table makes it a winner. Over the years some of the other locations have been good still, but the one in Idaho Springs has always been spectacular. Not sure what colorado style pizza is, but they have a couple of different crust styles. The Mamma Mia mountain pizza is my favorite. And Mount Evans to the south is worth driving to the top unless you are in the winter. I believe it is the highest paved road in North America, and the only permafrost location in the lower 48. The lake below the summit is a good stop, and if you can make it up the last little bit from the parking lot at the top you can claim you hiked one of the 14k peaks in Colorado.
4 Aces Diner in Lebanon, NH was a stop on the way back from a month long road trip that took us all the way up to Quebec City and down through Maine and Vermont. We had quite a bit of pure maple syrup with us and found this place because it offered it on the menu. The eclectic (to us) subway car dining room combined with excellent food was great. I still talk about the fried, homemade donut in maple syrup with whipped cream on top dessert I had there. I just wanted to taste it after my meal, but ended up eating the whole thing.
Salt Lick BBQ in Driftwood, Texas. I don't think the airport location does this any justice, so go to the original. A bit out in the country, but it feels like you are going to a hidden winery and being able to see in the pit was a lot of fun. We have at times ordered turkey breasts delivered out of state from here for Thanksgiving. I've had a lot of BBQ across the country, but the Salt Lick is my favorite. A few may have just as good or maybe even better BBQ in certain categories, but for overall experience and great across the board, can't suggest it enough.
Moonshadows in Malibu, CA mostly for the ability to sit at a pseudo private booth/table covered by curtains outside overlooking crashing waves, but the food was good too. I think this is also the bar that some actor (Mel Gibson??) got in trouble at, but that was after we went their the first time. Check out El Dorado State beack just north of here...along with being a very fine beach when it isn't high tide, it is where I asked my wife to marry me (as the sun set no less) many moons ago.
Early Girl in Asheville deserves a mention but it may no longer be the same. The first couple of times we went to it this farm to table type place was amazing. I'm not sure if the original owners sold it, or if the publicity they have received in big travel magazines have caused them to go downhill a bit, but the last two times they were just not nearly as good. We may go back, but in their heyday this was my favorite breakfast place anywhere.
Lou Manetti in the Chicago area has already been mentioned. I wouldn't maybe have it on my top lists in the country, but if you are in the area I'd certainly suggest going to it.
Trail Head restaurant? In Estes Park is another favorite. While the elk stew is good, and other menu items are above average, the real reason to come is the view of Deer Mountain while sitting on their deck. This is just outside the quieter entrance (from Estes Park anyway) into Rocky Mountain National park and is always a welcome respite after hiking or crossing trail ridge road. It is also well above the hustle and bustle of what is becoming too touristy downtown Estes. I think it is some sort of visitor center or something and they have a big gift shop, but we have just gone for the views and to get a decent meal in a touristy town.
The Original Mexican Cafe in Galveston, TX is memorable because it has a very nice blend of what I consider to be real Mexican food but also a little bit of southwest style flavoring. We eat at Mexican restaurants everywhere we go, and this is hands down our favorite. Don't forget to take the ferry ride over the Bolivar Peninsula, see the houses (and school!) up on stilts, visit the fort park, and drive for some nice scenery up to the bird sanctuary.