Rental car pick up/drop off?

Your title is ambiguous in that you don't mention cities, which would give you good responses from very experienced travelers. My advice would be to bus to Sienna from Florence and pick up the car there, and maybe to drop it off in the same place and bus to Florence/train to Rome.
You cannot drive in Florence without a permit, and the fines are very heavy. Rome is also a protected city, and if you even accidentally pass through a restricted area you will be fined and it will be added to your rental car bill! There are many complaints on this website from people who inadvertantly drove into restricted zones and were surprised by hefty fines on the credit card by the car rental agency. Again, try re-phrasing the title, and you'll probably get more detailed advice.

Shelly, I have to assume that you intend to rent the car in Florence. As pointed out by Donna, be very careful where you rent the car as most of the historical area is in restrictred zones called ZTLs. Very expensive tickets. Just make sure that you choose a place that provides immdiate access to the highways so that you don't drive in Florence. As for turing it in, you couldn't do better than Orvietto. There are rental car agencies very near the train station and its a very popular place to turn in the car so that you are not driving in Rome. Rome is about an hour away by train.

I would pick up the car at the Florence airport. There's too much chance of violating a ztl if you pick it up in the city. I believe there's a bus that runs between the airport and the SMN station or very close by. For the same reason, drop the car in Orvieto; and take the train to Rome. In addition to avoiding ztl's, you'll also save yourself the maddening experience of trying to make your way through a maze of one-way, narrow streets, poorly signed with crazed other drivers honking at you when dropping off the car. (Been there; done that.)
I would find a nice Tuscan agriturismo for the days after Florence. You might stop at S. Gimignano and/or Volterra on your way south. Montepulciano, Pienza, and Montalcino are all good choices for another day. Orvieto is worth a day itself. See the Graffiti Wall or Trip Advisor for some recommendations for Agriturismos. Buon Viaggio!

Pick up a copy of the Rick Steves Italy 2012 book RIGHT NOW and start reading it. Take it with you on the plane for the flight over. And consider autoeurope.com for renting a car. They get really high marks on the SlowTravel forum and they have really good rates. That's who we'll be using next spring. Happy travels and good luck.

I use AutoEurope for my rentals. They are a consolidator based in Maine. When you get on the site it shows the different car classifications and will show a diagram for how many people and how much luggage a car will hold. I would get the smallest car you can get away with, as some roads are very narrow and parking spaces are small. I recommend bringing a GPS with European maps or get one with your rental. I would pick up the car at the Florence airport, as was previously suggested. You can catch an express bus from the train station for 5€ per person. I also recommend dropping the car in Orvieto and taking the train from there to Rome. I did the opposite (picked up car in Orvieto and dropped at Florence airport) and it was very easy. A stay at an Agriturismo would be a good plan in Tuscany. Don't forget that the driver will need an International Drivers Permit, available at AAA.

Thank you for the responses. They are very helpful... I realize now that my title is very vague - I'll see if I can edit that.
Michael, I have Rick's Italy book on the kindle and will take it with me. I've read the applicable parts but will now dig in to the details. I do find it a bit harder to get into than the standard RS books though. Not sure why. Rosalyn & Andrea. Thank you for the recc on picking up the car at the Florence airport. This is exactly what I was wondering. It is a bit more expensive to pick up/return at airports but it seems like it will be very worth it to save the tickets and hassle. Will also check out the SIena option as well. Also, the suggestion of dropping of the car in Orvieto is a good one. I wasn't sure if I should try to get a bit closer in, but it sound like this is a good drop point. Michael, I will check into autoeurope for the car next. I'm a bit overwhelmed with my to do list and the order of trying to get things lined up. Got passport photos today in prep for getting the italy license. Reminded me also to get italian maps for the gps. Thank you. Thank you again for opening the vaque post and helping a long time RS traveler - who hasn't been to Italy in 20 years. Looking forward to it! Shelly

Hi Shelly, Dropping off your car at Orvieto is a great plan. Car rental offices across the street from train station, very easy to spot. We also used Hertz but booked thru Gemut. Were very happy with the price and the arrangments, but brought our own pre-loaded GPS. I would plan to get to Orvieto early in the day so that you can ride the funiculare up to the hill town and spend lots of time there. We really enjoyed the underground tour, the spectacular Duomo and the many wine and deli shops offering tastings. Great shopping there in a very compact area. From there it's a straight shot to Roma via the train. Enjoy. Sherry

Shelly! I'm so very happy you had so many responses to your question, as I was concerned in the beginning! Don't get overwhelmed -- have fun, rent that car, and enjoy the vaca of a lifetime!

It sounds like you may have a handle on the car rental now. I also use AutoEurope or Kemwel. You can compare their rates online. Pick the car up at the Florence airport and drop it off at the train station in Orvieto. Get a Michelin, or similar, map at a Barnes & Noble. Use the DBahn site to check out train schedules. Here's the website: http://bahn.hafas.de/bin/query.exe/en If you click twice on the arrow in the red box on the left, you will get a complete list of all the stops that train makes. I print these off and take them with me. Makes it easier to purchase the tickets and also to know what stop is before the one I want. We stayed at Hotel Valentino in Orvieto. They have a triple room with frig, a/c and in a quiet area of town. Maybe they have a quad. What other towns are you planning on staying at in Tuscany. If you need hotel/lodging recommendations, send me a personal message. Have a great trip!

We got a very good rate from the Avis car rental in Sienna.

In all my trips to Florence, except the first one, I rented my cars at the airport. The first time I rented in town, but only that once because I had to drive out of the city, never again! Most airports are easy to get to and easy to rent cars.