Reconfirm all your reservations a week or two in advance. I have had to have soooo many reservations corrected because they did not have the right month, day, or even year! I think that the way we format our dates differently is somewhat to blame. Although, I think carelessness is more likely the cause.
DO NOT DRIVE INTO THE CITY CENTERS OF MOST OF THE HISTORIC CITIES!!! They have "limited traffic zones" (ZTL) Zona Traffico Limitato. Check out this helpline to get more information. For instance, The entire central part of Florence is a ZTL. But it consists of several different zones within. Every time you pass from one zone into another, a camera will snap your picture and you will get a $125 fine!! One drive across the city center will net you several fines. You can be billed up to one year later and your rental company will turn you in (for a fee), or they will just charge your credit card. One way to avoid this is to have whatever hotel you are staying at within the zone notify local authorities that you have legitimate business there. But, double check to make sure that this has been done. If you are not staying there, you should park in a structure outside the zone and walk or take a taxi to your destination.
On the advice of my neighbor who lives permanently in Italy. Don't dress like a tourist (ie shorts, sandals, t-shirt, sweat suit, white sneakers, etc..), pack lightly (I learned my lesson), wear your clothes more than one day (no one will ever know), watch your luggage on the train, don't accept anything from strangers, walk across the street with authority (but watch out!), and put away your valuables (neck wallet or money belt), or better yet lock them up in the safe in your hotel room, and leave the expensive watches and jewelry at home (thieves can spot a fake Rolex from 6 ft. away).
Since you are driving, I strongly recommend using a GPS.