What Airport To Fly Out Of?

Pisa would be closest. Depending on your departure time for your flight, you might consider staying in a hotel near the Pisa airport (as you wisely did in Milan) so as to avoid any hassle with possible traffic jams. Perhaps your agriturismo could help you iron out some details?

I think the biggest limiting factor will be availability on the transatlantic segment of your flight and that most flights are going to leave fairly early in the morning. Driving into Florence the day before and staying your last night there is a great way to go, however, you might have more flight options from Rome or Milan to use with your miles.

Which airline you have miles with?
The closest airport is Florence, but mileage award seats are often limited, and Rome will offer the higher number of flights anywhere. Pienza is between Florence and Rome, slightly closer to Florence but not by much. Whichever airport you choose, you cannot spend your last night in Pienza. You need to move closer to the departure airport the day before departure.

Yes I think you may find with an award booking your choice will be restricted.
Rome may in fact be your best option, as Roberto suggests. Dump your car the day before and train in into Rome.

Driving to Rome from Pienza is easier than taking the train. If you intend to spend the night in Rome you should return the car at the Tiburtina station. If you have already seen Rome and don't care to spend the night there, you could spend you last night along lake Bracciano, then return the car to the airport the morning of the flight. From Bracciano to Fiumicino is less than 45 min drive.

I like the idea of adding Rome to the list of possible departure cities. My only concern is that I'd like to get the car checked in the day before we fly out. Ideally, we would check in the car, find an inexpensive hotel nearby and then take a bus or taxi to the airport the next morning. The other issue is we will be flying home on a Sunday. I think many of the car rental companies except for a few major ones at the airport are closed on Sundays and some maybe even close early on Saturdays. Any more suggestions on how to do this?

Let's assume you fly home from Rome on a Sunday morning.

Option 1: Stay in the city of Rome. In this case you would drive from Pienza to Rome on Saturday and return the car at the Tiburtina station (easiest to access from the freeway). The Europcar office at Tiburtina for example closes at 5:30pm on Saturday. Once you return the car take a taxi to a hotel in the city center, spend the evening in Rome, then the next morning take a taxi to the airport (30 min for 48€).

Option 2: Stay in the countryside near Rome airport (I suggested lake Bracciano, 40 min away). In this case you drive there still on Saturday but keep the car, then on Sunday morning you drive to the airport, return the car at the airport (always open) and leave.

Option 3: Stay at an airport hotel at the airport (Hilton) or very close to the airport. In this case you would still go on Saturday. Then it's up to you if you want to return the car at the airport on Saturday then go to the hotel by taxi/shuttle or if you want to keep the car at the hotel and return it on Sunday morning before the flight.

There is no direct flight from Italy to Seattle. I would go for the nearest airport which has direct flight either to Amsterdam, Frankfurt, London or Paris. And from there there are direct flights to Seattle. Amsterdam is the easiest to change planes.

Staff here also prefer to connect at one of the European hub cities that Ilja listed. By avoiding connections in New York city or another USA/Canada location, you avoid delays common to some of those airports, avoid extra time for USA customs and immigration clearance at the connection point, have international services standards (such as entertainment and meals) all the way home to Seattle, and may also be saving time with the "polar" flight route.

If you're booking through Alaska Airlines Mileage Plan, then Delta/KLM is one of your covered options, as well as some of the best flight connections to/from Seattle. I see that Delta/KLM has a code-shared connection Pisa-New York-Seattle, but if you depart from a larger Italian city, you can go via Amsterdam or Paris. If you fly from Milan, then Delta/KLM has connections from Milan Linate airport via Amsterdam, better than route options from Milan Malpensa airport.

If you like the Delta option via Amsterdam, the closest airport to Pienza is Florence. There are 4 daily departures from FLR to AMS with KLM (Delta partner).

Since you are likely to have to take the first flight out of FLR to AMS, you may have to move to Florence to spend the last night. Pienza is 1.5 hours away from Florence.

FLR also has 6 daily flights to Paris CDG (AirFrance) and 5 or 6 daily flights to Frankfurt Int'l-FRA (Lufthansa).

Seattle has flights to both Paris CDG (Delta, which is AirFrance partner) and to FRA (Lufthansa & Condor).

Not sure which mileage plan you have, but if you have Delta, there is a higher chance that award ticket seats are more numerous via ATL or JFK. Not ideal, but when you travel with mileage awards, sometimes the options aren't the best.

Thanks for the great advice. I don't have enough miles in Delta or Alaska but I have tons of AA and United miles so I'll probably look at Lufthansa. It's good to know Rome is a doable option.

AA is partner with British Air which flies from SEA to LHR.
The flights from Tuscany (PSA or FLR) to LHR are limited. Most are to the other London airports.
If you fly BA your better options from/to LHR are either Rome FCO or Bologna BLQ.
AA flies to Rome from JFK and ORD (seasonal).