Going to Umbria/Tuscany for 1st Time for 2 weeks

What looks good to you? Have you pondered driving yet? There is no reason you shouldn't explore Tuscany and Umbria on your first visit.

Given that these areas cover a large area and include many, many historic and interesting towns, cities and villages, you can easily spend all of your vacation there. With no other information to go on, no one could suggest an itinerary, if that is what you are asking.

When planning your itinerary, give close consideration to your transportation logistics. A car will be a great hindrance in the cities, but may be a necessity in the rural areas. Learn about the Italian trains and the Italian driving laws.

We've spent a week in Tuscany (including three nights in Florence) and we're getting ready to spend a week in Umbria this summer. Do you have flights yet? What are you interested in seeing/doing?

Tuscany,
Florence, Siena, Lucca and Pisa.
Umbria,
Spoleto, Perugia, Orvieto, Gubbio, Assisi

We have done this 3 times -- 35 years ago we rented an apartment outside of Siena in a small village and toured Tuscany for a week; about 20 years ago we rented a cottage outside of Lucignano and did the same. And when I retired 10 years ago we rented an apartment in Montepulciano for two weeks. Ideal to be in a smallish city or town where you have easy access to the road out of town but also have a few restaurants. Montepulciano was wonderful for this. Our apartment had a little balcony with room for two chairs where we could look out over the Val d'Chiana and enjoy a glass of wine before heading out for dinner.

With two weeks you could rent for a week in two different areas -- there are so many abbeys, gardens, picturesque towns in Tuscany -- You can go to a new one each day.

Flying in and out of Rome works. You’ll need to rent a car so read extensively on ITs ZTL zone laws to avoid costly ticket(s).
Do not drive the day of arrival if taking an overnight flight from home; better to be safe than sorry. You can take a train from the Fiumicino Airport to Rome’s Termini station and transfer to Assisi (3h 15m).
Rent a car in Assisi and drive to Montepulciano (1h 30m) and make this your second base to explore the Tuscan countryside. A good day trip option is Pienza’s old town (30-minutes).
When you’re ready to leave Montepulciano get on the Sienese Crest Road and drive to Siena. This is why people go to Tuscany to see the many varied landscapes of rolling hills and scenic wonders. Don’t get an early start in case there’s fog. You won’t be able to park your car in Siena’s city center but you can park outside of it but still sleep inside the center. Siena is magical at night after the day trippers leave. While in Siena visit the duomo and hang out at Il Campo square at night. Good day trip options from Siena are Volterra (1h 15m). Another good day trip is San Gimignano (1h 30m).
Drop off your car in Siena and take a direct bus to Florence (1h 15m) and make Florence another home base to sleep in to finish exploring Tuscany. The two must-see sights in Florence are the Uffizi Gallery and Accademia. Buy tickets for the former two-months out. Good day trip options by train are Pisa by direct train from Florence’s SM Novella station (1h). Another good trip is Lucca (1h 30m) but you’ll need to get an early start for a direct train from the SM Novella station.
You can then go back to Umbria from Florence by direct train to Orvieto (2h 15m) and sleep there before going back to Rome (1h 30m).

If coming from the US my suggestion would be to fly into Florence and spend a few days there enjoying the beautiful Renaissance city. Then take the bus or train to Siena for another few nights and collect your car there as you begin your exploration of the Tuscan and Umbrian countryside.
You don't need (nor do you want) a car in the city, but you really need one in order to see the countryside and to visit the hilltop villages. Do your homework in advance regarding Italian traffic rules - especially as regards the ZTL's as was mentioned - and you should do fine.
I'd book a vehicle with automatic transmission too just to minimize the aggravation - the default rental will be a stick shifter - and ensure that you've sorted out the matter of insurance as well.

When are you planning to go? What are your main interests . . . scenery? wineries? history? art/architecture? food?

Have you traveled in Europe before?

Are you planning to rent a car? Do you have experience driving in hilly areas (urban and rural)?