Provence-Vaison La Romaine-Cassis-so much to do so little time

You need to give more information before anyone can give you advice on some of your points. Is the 4 days 4 whole days; i.e., 5 nights; or is that 4 nights; i.e., 3 whole days? "Relaxing" and "see as much as possible" are rather mutually contradictory. What exactly do you want to see?
That being said, here's my personal opinion on some of the places you've mentioned. I was underwhelmed by Avignon. The papal palace is mostly empty; and the half-destroyed bridge can be viewed in a few minutes, . If you want to visit a city, Arles is much more interesting.
The Camargue might appeal to you. It's a nature reserve with a great variety of water fowl, including flamingoes. You can hike and bicycle there, and it offers a huge contrast to the Provencal cities and towns. I believe you can get there by bus from Arles.
I'd skip the wine tour.

Rick's accommodation listings and other practical details for Cassis are only in his Provence book (which also covers Marseille and a few other destinations that didn't fit in the France book). Each is described with various caveats; for instance www.legolfe-cassis.fr can be a good value if you're able to book one of their view rooms. www.hoteldefrancemaguy.com will pick you up at the train station if you book ahead. The train ride from Avignon to Cassis takes roughly 2 hours. The train station in Cassis is further out of town than the bus stop that heads toward Marseille.

This is always a tough call b/c preferences of cities are so subjective. I would agree with the other poster that we were also underwhelmed by Avignon and did a day trip to Cassis and really enjoyed it (Friday is also their market day, which was fun to stumble upon). If I'd have to choose between the two in hindsight, I would pick Cassis over Avignon but I also love the ocean. We thought a day trip was more than enough time to take a Calanques tour and walk around to get a feel for the town, but we just stayed in the main tourist area near the waterfront (and didn't lounge at the beach).

As for the wine tour, we did one of those too and it was our favorite activity, but we also love Southern Rhone blends, so we might be more passionate about it than most. But in addition to the wine, it was also a nice way to see the beautiful landscapes and it helps to ensure you're going to a great winery.

We were based out of Isle-sur-la-Sorgue, which was central to both areas, but we also had a car (Isle does have a train station but you'd have to go to Avignon, I believe, to get anywhere else).

Thank you for all of your comments, everyone. Sounds like a day trip to Cassis is doable and worthwhile. Also, I'm so glad to hear the Cotes du Rhone is as beautiful and scenic as it sounds in the guidebook. As for Avignon, it's just a convenient place to hang out, and store our luggage while we await an evening train back to Paris-but I appreciate your thoughts, so we will not feel we are missing anything by not spending more time there.

One additional question...does Marseille have any good hotels, if those you mentioned in Cassis were not available?

Thanks again.

If the two Cassis hotels aren't available, you should look for others in Cassis on Trip Advisor rather than tramping back into Marseille for the night. There are more than just those two that are good. It's wonderful to wake up in Cassis.

Thanks again for all the suggestions. We decided to spend two nights in Cassis and found a great spot using AirBnB.
I have all of our hotels booked - now, if only I could get my train tickets booked through SNCF, I'd be set. Having a lot of issues with their website. I think I've finally figured out, I have to book one trip at a time, and one booking per day - waiting 24 hours in between each booking. If this doesn't work, I guess I will book through Rick Steve's.

I would spend more time in provence and skipping avignon. Arles is a more interesting lger town. But if u decide on cassis while it takes a fair amt of time in your train transport it is a gentle, small relaxing seaside village. You must incl a boatbride tomat least 3 calanques, that is the draw. I was there last yr for 3 nites . Marseille is very gritty so bypass anytime there for sure. Ck ahead forbyour busschedules frpm marseille train to cassis i believe it is spotty and may involve a transfer. We drove which was uneasy in marseille but ok otherwise.