It would help if you told us what your main interests are and how long a trip you are thinking of. Until then, I'll just toss out some observations.
You said your wife has been to Paris and Belgium. Is she pushing to return or more interested in somewhere else? Paris is my favorite city so that would be first on my list. I've never spent less than a week there at a time and still haven't seen everything on my list. Also there are several good day trips. It's easy to go by train from Paris to Belgium and on to the Netherlands.
Spain - There are fast trains, so you can go from Barcelona to Madrid to Andalusia (Seville, Cordoba) very easily. Toledo is 1/2 hour from Madrid by train. After Paris, I think Andalusia is my favorite part of Europe. I couldn't believe it when I got there, but I liked it more than Italy. To get to Lisbon from Spain, the choices are slow bus travel or flying. You'd think it would be easy to see both countries in one trip, but it really isn't.
Vienna is between Prague and Budapest. With 2 weeks you could spend plenty of time seeing these three great cities and mostly easy walking. This is a very popular route.
Italy I think Italy is a wonderful destination - I went for the first time in 2008 and will be back next week for my 5th visit. However, it would probably be the hardest on your legs.
Lastly, I find that Frommer's website is really helpful for getting an overview of a city. There are suggested daily itineraries (though I don't know who could fit in everything they list in the time they allow), and a list of attractions, with descriptions, that they rate from 0 to 3 stars. Or borrow guide books from your public library and flip through them, see what really grabs you.