Which is the best airport to fly into for the Tuscany area?

If you're just going to Tuscany and not Rome or Venice, then Florence or Pisa would be much closer and easier.

If Florence or Pisa are not an option for you, Rome is the better choice. 1-3 hours will get you just about anywhere in Tuscany by train or bus from Rome.

In addition to Florence and Pisa (which are actually in Tuscany), Bologna airport is not far. If you have to change planes anyway, it may not even cost more to fly into one of these, vs. flying into Rome.

Unless you're coming from Philadelphia or JFK, Venice has no nonstops from the US, so you'd have to change planes to fly there as well. Pisa gets a few nonstops for a couple of months in the year, but Rome and Milan have by far the most service from the US. Of those two, Rome is closer.

Before booking flights, you should figure out what you want to see. If you're seeing other places besides Tuscany, that will dictate the best airports to use. For instance, if you're starting in Venice, then going to Tuscany, then ending in Rome, you would fly into Venice and out of Rome (an excellent itinerary, by the way). Note that flights departing Venice for the US (unless you're on one of the nonstops I mentioned above) often leave very early since they have to make a connection. Getting to the Venice airport early is a hassle and can be expensive. Getting to Rome airport early is easier and cheaper.

@Harold, thanks for reminding me, on one of my trips to Tuscany we did fly into Bologna airport and that was also easy.

We'll be staying in Pienza and visiting the wine region of Montalcino & Montepulciano, also going to both Florence & Venice. Not sure where we'll fly out of, Charlotte or Atlanta most likely. It sounds like we should look fly into Rome & pick our car up there. Was just trying to shorten the drive from airport to Pienza, but heck it'll take us at least 2 1/2 hrs just to get to an airport from where we live.

If Venice is part of your itinerary I would visit Venice first and therefore fly to Venice first. In Venice you won't need a car and that visit will get you accustomed to the time zone without having to drive upon arrival. Then you could rent a car in Venice and drive to Pienza (4hrs mostly freeway). Alternatively you could take a train to Florence or Chiusi and rent a car there ( although at that point I would rent in Venice and drive and save the train fare of 45€.)
Your departure airport could be FLR or Rome FCO. Pienza is about 2.5 hrs from Rome airport by car and just about 1.5 hrs from FLR airport. Pisa and Bologna are almost as far as Rome from Pienza in terms of driving time, so you might as well use Rome at that point.

Looks like you're on the right track.