Road trip: Frankfurt to Italy

I assume you mean you are renting a car... If so you will need to check out the drop fee for renting in one country and dropping in another. It can be quite high. You can plan your route so you do some kind of a loop with Germany, Austria and Switzerland, then drop your car and take a train to Italy and get a different car to tour there and then drop in Rome.

If you plan to fly into Frankfurt, rent a car, and hit the road, please don't. Stay at least a day or so there to get over jet lag and get your body and reflexes back to "normal". It's not the easiest place to drive even when one is 100% on his / her game. Just food for thought.

Thank you all, I should have clarified. We are flying into Frankfurt, staying with family for a few days, and then renting a car and driving to Umbria. We are being dropped off in Florence to catch our plane back and then the car will be driven back to Frankfurt by the family. So just wondering if there's a 'not to be missed' spot on the way from Frankfurt to Umbria, by car.
Thanks!

The Berner Oberland area of Switzerland -- particularly Gimmelwald and Murren if it isn't too far off your planed route. If it is, go there anyway -- outstanding scenery.

You can choose to drive right through Switzerland - Bern, Luzern, Lake Como or go through Austria - Munich, Innsbruck, Brenner Pass, Dolomites, Lake Garda.

Where to stop depends on how long you want to spend on the journey and there are many options!

Maybe Engelberg, Switzerland and go up the Titlus, that would only add a few hours and is about half way into a nearly 12 hour drive.

It will be a great drive with awesome scenery!