How about Ste. Genevieve MO? Settled c1735 has the greatest concentration of French Colonial buildings in North America.

On the other side of the river and just a little upstream is Fort des Chartres, built 1720 when the French controlled Louisiana Territory. It's a few miles from the road.
http://en.wikipedia.org/wiki/Fort_Chartres

The Chain of Rocks Bridge north of St. Louis used to carry Route 66 across the river. Now it's open to hikers and bicyclists, so you can walk across the Mississippi.

St. Louis of course has tons of nice places to stay and to eat, and is easily worth its own weekend.

My husband wasn't really wanting to stay in a big place like St. Louis we were trying to stay outside of there. Thank you for the info on St. Genevieve and Fort des Chartes this is the info that I am looking for. Now anything on the outskirts of St. Louis would be helpful.

What does anyone know about Hannibal,MO or Alton,Mo and Keokuk,IL, Muscatine, Rock Island, Bettendorf or Clinton,IA this is the route we were planning on taking. If we leave early on a Friday the St Genevieve would come into play but if we leave on a Saturday we would have to be past St. Louis.

You mean Alton IL, I think. I like Alton. There's a casino there if you like that sort of thing, and lots of antique shops. One of my husband's old buddies runs a restaurant/lounge there called the Bossa Nova.

Probably the only World Heritage Site along the Road is at Cahokia Mounds, where I am thinking about joining the autumn equinox sunrise watching tomorrow at 0620. Mound builders lived here. Very worth small detour.

Trail of Tears State Park, south of Ste. Gen,, has interesting history and might be good if you just need a break.

Hannibal has nice B&Bs, and is worth a stroll past Twain's childhood home. I am planning a family reunion and thinking about having it there.

Let me put in a word for Clarksville, though, a bit downriver. Right on the river, a classic old river town and artsy craftsy.
http://www.clarksvillemo.us/index.html

I've only ever driven through Keokuk and Rock Island, sorry. I hope someone can help you with those.

OK, just a bit more about IL north of St.Louis:
There's Pere Marquette State Park, with cabins, a lodge, and hiking. You're there at the beginning of our local Leaf Peeper season, though, and might be sold out.

That stretch of road past Alton is lovely in the fall, with limestone bluffs, beaver dams, people out cycling on the bike path. Weekend traffic can be a mess, though, full of people driving up from the city. Try to time it so you're not going south in the late afternoon or evening.

Hardin IL has fun little catfish eateries. It's right down there at river level.

Elsah IL, tucked in between the bluffs, is worth making a left and driving or strolling through to stretch your legs.

One more thought about Ste.Gen: there's a ferry just north of town that might make it a possible stopover for coming back south.

Thank you, Thank you i read this to my husband and he really likes what you had to offer us. I'm gonna print this out for our trip lol. Again thank you very very much.