Avignon, France to Lake Como, Italy

It would be helpful to provide more detail. How long a journey do you plan? How many stopovers? By car or by rail? If you are going by rail, you can take trains along the coast to Genoa, then a train to Milan, and finally a train to Como. Or you can go north to Lyon and from there to Como. In any case, you can play with various possibilities by consulting the DB website (see the link in Rick's "favorite links" section), and by googling the "Man in seat 61" and browsing his site for ideas.
I have never driven the route, so I will leave that for others. However, if you decide to drive, and if you plan a one-way trip, double-check the rate with a rental car company before you make your final decision, as cross-border drop charges can be quite high.

Fly, drive, take the train, or walk. If you have money, taxi or chauffeured car. There is no through water system so boat is out.

My intent is to travel straight to Lake Como with no overnite stops on the way. I would prefer to take the train...second option would be to drive the 260 miles.

If you want to train, the DB schedule shows that the trip will be at least 8 hours, with some changes of train necessary.

Thanks..exactly what I was looking for...