For this vaycay we rented apartments in each city rather than staying at hotels. I did this in Paris and found my experience to be so much better because of it. Though the five flights of stairs is something I will never get used to.
Rome we had a lovely apartment in the Testaccio area. According to Fodor's this area isn't really explored by tourists. YAY! We ate mainly within a few block radius of the apartment, and often had difficulties finding anyone that spoke English. AMAZING!
Florence was again, in a lovely area, on top of an amazing bakery and across the street from a delightful deli. Milan was right off the tram line and so accessible. Venice was cool, but three flights made for some difficulties for my parents. (Don't get me wrong, I hate stairs too. They are in fact, one of my biggest fears. Stupid right?)
The thing all of these places had in common was that there wasn't another tourist in site when we left our room. For a few days in each city, we got to kinda see what life is like in each city. What living in Rome, Florence, Milan and Venice would be like.
So thanks VRBO.com and homeaway.com - you have totally changed the way I travel.
Bonus - each apartment was close to half the price of a hotel.