Most road signs in Italy are self explanatory and you'll understand them easily. Visit this Wiki page to see them all. Speed limit signs appear as a round red circle with the maximum speed. The highest speed you can go is 130kph (81 miles per hr.) on the autostrada. You will often see signs that will slow you down to 110kph (68 mph) or even 80 kph (50 mph), and much slower on rural routes, particularly when coming into small villages. All speeding violations are captured automatically (by video).
Streets marked with ZTL are limited to authorized vehicles ONLY, and the fines are quite steep for driving in any unauthorized area. Do not drive on any street marked with a sign that says ZTL.
Entering the toll booth and getting your ticket is very similar to the US. Do not use the Telepass lane when entering the toll booth area. Use the lanes with the photo of coins or change and symbols for credit cards. (see photo to the right). When you enter the freeway, pull up to the ticket machine, the ticket may automatically appear; if it doesn't, press the big red button. Take your ticket and drive off. When you exit the freeway, drive to the cash/credit card lane and insert your ticket. The price will be digitally displayed. Pay with cash or credit card and exit.
It's easiest to park in large parking areas or garages (big blue P, Parcheggio sign) and purchase a ticket at the kiosk that provides a ticket that you will use to pay when you return. In Italy, street parking is designated with either blue, white or yellow lines. You can not park in yellow-lined parking spaces. These are for residents only. Blue and white spaces are for public use. White is free, and blue is paid. If you park in a blue spot, you will need to find the nearest parking kiosk to pay for your stay. Most accept cards for payment, pay with your card, and then place your ticket in the car on the dashboard.
US citizens should have an International Drivers License--very easy to get at any AAA office. Collision and Damage insurance is required in Italy. While slightly more expensive, opting for an all-inclusive car rental insurance is usually the wisest choice for complete peace of mind during your trip.
Most rental cars will be manual (stick) drive. Be sure to specify when you are purchasing the car rental. You can prepay for the gas (extra charge) or fill up your car before you return it. Always ask what kind of gas is needed for your car, (most will be diesel). Be sure to bring your International Drivers License and your own license. Ask how to call for assistance if needed.
When you locate your car, take pictures of all sides so you have a record of what the car looked like when you picked it up. Check for any damage. Be sure you note any damage you see with pictures. Any existing damage should also be noted on your rental contract. If it isn't, speak with the advisor. It's important to take a few extra steps to cover all your bases.
Take plenty of time to familiarize yourself with the car before you leave the parking lot, (how to start the car, what kind of gas, is there a spare tire, emergency numbers, etc.) The instrument panel speed dial is in Kilometers per hour. The conversion is roughly 100kph = 65mph. Google Maps works perfectly in Italy and remains in English mode. If you use Android Auto, or a similar iPhone product, take time to set that up before you leave. (you must have a phone data plan from the USA to use Google Maps with voice directions).
Rest areas in Italy are busy places. A great place to buy gas or just stop for a break! ("Autogrill" is very popular and it is fun to stop and explore!). Some are small, and some are huge and offer sit down dining. In almost every rest area along the autostrada, there will be an entry and an exit door, and the cashier for purchases you're taking away will be near the exit. If you want to purchase something to eat or drink from the cafe, you will pay for it first, and then show your ticket to the barista.