You don't say how old your kids are but one thing that comes immediately to mind is Hannibal, MO, home of Mark Twain.

Mississippi Palisades State Park in Illinois has some really nice views:

http://www.stateparks.com/mississippi_palisades.html

Farther south, Pere Marquette State Park is very nice:

http://www.greatriverroad.com/Pere/PereIndex.htm

You also did not say what time of the year. Fall is great with festivals the first 2 weekends.

In Iowa. Lansing is a nice town with nice places to get coffee and lunch/breakfast.

Stop in McGregor. Definitely eat at the Twisted Chicken. Yes that is the same of the restaurant. And if you go for dinner it is best to get reservations. They change their menu everyday. Meals from $16-30. Worth every penny. They even rent rooms.

Go up to the top of Pike's Peak STate Park. Nice view any time of the year.

Clayton has a great B&B the Claytonian (address is actually Granvillo in the phonebook).

Have lunch in Guttenberg on the river.

Have dessert in Balltown at Breitbach's, 6 generation restaurant. they make homemade pie. Check first they have had some drama in the past few years. Had a fire and burnt down the original oldest bar in Iowa. Rebuilt. Burnt down again. B&B in an old rectory (Heavenlee B&B).

Dubuque, IA has the GReat Mississippi River Museum and Aquarium. Good for the whole family. The large hotel there (cant remember name) has a water park indoors.

Prarie du Chien, WI is nice.

If you cross further down take the Cassville ferry (not sure of hours)

You can also cross at Cassville to WI side and miss Balltown.

Drive down IL side and hit Galena. lots of tourist shops and restaurants. but nice town.

Need to go through Sabula either way. Sabula is Iowa's only island city.

Savanna, IL is home to Poopies Bar and Grill. Kind of a Harley shop/restaurant. Music on the weekend. Not really a children's place at night but fine for food. That way you can get a T-shirt that says you ate a Poopie burger.

Le Claire/Princeton IA has lots of nice shops and restaurants to eat.

Fort Madison has a fort to tour. Historic Hotel on the riverfront. Great restaurant in it. Starts with an A. Sorry.

Navuvoo, IL is a Mormon settlement. They have an old village that is a tourist site. Show how to make bricks, blacksmithing, candlemaking, etc.. Good for the whole family.

Thank you! We'll be traveling with four kids, two 7yos, a 5yo, and a 4yo.

I think we'll be heading southwest from Madison, WI to around Dubuque and then continuing south along the GRR to St. Louis.

Is Hannibel worth a stop?

I second the Mississippi River Museum in Dubuque, especially with kids. There is also a great boat tour of the Mississippi back waters that leaves from there.

The hotel by the museum is the Grand Harbor. There is a great place to eat on Hwy 35 just outside E. Dubuque. It is called Thumser's 19th Hole. Great hand patty burgers!! The meat is ground on site. They also have an adjacent miniature golf course.

Great! Thanks!

If you were driving from Dubuque to St. Louis making stops along the way (River Road the whole time), any idea how many hours/days it is?

Taking Hwy 61/151 to I-80 to I-55 takes 5-6 hours depending on traffic and construction. So taking the GRR I'd gestimate 8-12 hours depending on stops, sightseeing, etc.. Which side do you plan to take; Iowa or Illinois? That will also make a difference in driving time.

Sorry, forgot to mention earlier, this is in August.

I'm thinking we'd go down the Iowa side, but how easy is it to cross over?

It crosses over at the Quad Cities among other places. I've attached two maps.
http://adventure.howstuffworks.com/iowa-scenic-drive-great-river-road.htm

http://www.milebymile.com/main/United_States/Illinois/byway/Great_River_Road__hyphen__Illinois.html

Thank you! Is the area where the great rivers meet pretty interesting?