Where to pick up and drop off rental car

As long as you are not going to deal with city driving and the camera-controlled ZTL area, you should Pick the car up at Florence airport. You can use the tramway line to get there from SM Novella station.

Drop off either at Orvieto or Chiusi and take a local train to Rome; these are small towns in the countrywide, you'd better check the operating hours.

Any airport rental will come with additional charges/tolls/taxes.
Hertz has a location on Sansovino in Florence that's about a 2 mile taxi ride from the train station. They give you directions out of the city to avoid the ZTL in the center city.
The best place to turn the car in is at Hertz in Orvieto that is located across the street from the train station. It takes 70 minutes to get into Rome Termini from there. Orvieto's also a popular hilltown to visit.

No need to go to airport- that will cost more
We picked up at Hertz Sansovino location. Very easy from there no worries about ZTL, was a short cab ride from center
Orvieto or Chiusi for drop off

We always book thru www.autoeurope.com- very knowledgeable and helpful with excellent customer service and usually best rates
(Although I think they no longer deal with the Hertz location in Orvieto)

I'd go with the tram to Florence airport unless you have some Italian city driving experience. It is true that an airport rental should cost more due to special taxes and fees, but the reality is more complex. Some comparisons I've done suggest rental car companies may raise their in-town base prices to negate (profit from) the difference. True comparisons are just about impossible because price quotes will generally have a footnote that some local fees may not be included.

For the pickup there is a Europecar location outside the ZTL that is closer than the airport. Address is Via Enrico Forlanini, 2, Florence. We are traveling in April and will be picking up and dropping off at that location. I don’t have a recommendation for drop off on your way to Rome. Safe travels.

There Is a T2 tram stop quite close to Via Forlanini, It seems a sound advice.

Why not the Hertz location at Via Borgo Ognissanti?
I've got a rental lined up there, easy walking distance.
I assume they'll give good directions for getting straight out of Florence?

We picked up and dropped off a rental car at the Florence airport last year, and we won't be doing that again if we can avoid it. Dropping off was okay (but then the airport itself was a nightmare afterwards). Picking up was the problem. The rentals aren't at the airport, so we had to take a very slow, very crowded shuttle bus to the actual cars. Then we had to get in very long lines to get the car.

We rented two other cars on this trip, and both we picked up walking distance from a train station. Much smoother.

We used the Borgo Ognisanti location a few times, easy out to the highway.

If you're coming from Tuscany with a car, dropping off at Tiburtina is not difficult. It's not far off the main highway and there are no ZTLs lurking nearby. Easy to take a taxi into the centro from there.

I picked up at Hertz Borgo, the lines were long and the car situation was all mixed up, but patience is a virtue and driving out of the city was not too difficult. Let’s put it this way, if you can’t drive out of Florence you’ve got a lot more complexity facing you down the line. Most Tuscany tourist towns are traffic limited so be prepared with routes to planned parking locations. For example, if you select a parking garage outside of Sienna and plan your approach, you can avoid much difficulty circulating around. Driving around searching for a parking area is very difficult when much of the street system is closed to vehicles without a ZTL permit. I agree with previous poster, reasonable to drive to outskirts of Rome.