Here are some good things to see driving south from Vancouver

Mt. Rainier
The Columbia River Gorge
The Oregon Coast from Cannon Beach to Brookings
The Redwoods of northern California
Sonoma and Napa Wine Districts
Point Reyes National Seashore

HTTY

August? February?

Yes, time of year can make a big difference . . .

Seattle and Vancouver have good public transport. I have never driven a rental car in Vancouver. Ride the Amtrak train or bus from Seattle to Vancouver. When you leave Vancouver you can take the train to either Seattle or Portland to rent your car.
Have you found a deal on the rental car where you don't have to pay a drop off fee in San Francisco?
I like HTTY's list. We still need to know what month.

Don't know about the drop fee, but if you rent from one of the majoprs with a downtown location it will be cheaper than renting at SEATAC.
Both Seattle and Vancover are very walkable cities as well as having good transit systems.
In Vancouver visit Granville Island, you can take the water taxi from several locations. Also Stanley Park.
If you go inland, consider Mt. St. Helens in addition to Mt. Rainier.
The Columbia River Gorge is well worth the detour at least as far as Hood River.
In CA I'd also recommend getting back to Highway 1 above Ft. Bragg and follow it south past Mendocino, Ft. Ross and Bodega Bay. From Bodega Bay cut over to the Sonoman/Napa wine region and thence into The City.

In Vancouver you can get tickets for a " hop on- hop off trolley" meaning that you buy a ticket and trolley will take you to many of the tourist sites- when you have spent the time you want at one site, you get back on the trolley to the next site- tickets available at many of the downtown hotels. I thought it was a great way to see the city without driving. It takes you to Granville Island and ticket includes ride over.

I have to say that sometimes the trolley gets very crowded and is full when it arrives - so you have to wait for the next one. That was a bit inconvenient at a couple of spots but it all worked out.

Oregon does have a beautiful coastline- however, in some areas there is not a lot to see but trees as you drive along. I think the area between Florence and Coos Bay is one of those areas unless you are willing to get off the road and check out some areas-

If you drive the Oregon coast- my favorite beach is Devils Elbow State Park just north of Florence- beautiful light house, small beach on a cove - some hiking trails- great place for a picnic- or--- you can stay at the lighthouse keepers house which is a B&B- they have a fabulous breakfast in the AM.

Are you really bent on going to Vancouver? You could take a ferry from Seattle to Victoria and not a rent a car until you get back to Seattle- just a thought.

From Vancouver you have the choice of staying more inland to see Mt. Rainier and Mt St. Helens with a cut to the coast via Portland; or going to the Olympic Peninsula for the mountains (Hurricane Ridge), the coast (Neah Bay with an interesting museum and a walk to the western-most point of the lower 48 States), the rain forest and then a drive down the coast.

http://www.flickr.com/photos/mksfca/sets/72157622991196341/show/

Many thanks to all for the valuable advice and suggestions. We arrive in Seattle end of September and fly out of San Francisco mid October. Yes we like to minimise car hire but prefer the flexibility to train travel which we have done in the past. The one way hire adds around $100 which is cheaper than the fuel and hire of a two way trip. Thanks again.

When you get to Vancouver, if you have time - a drive/bus ride up to Whistler/Blackcomb ski area is a beautiful trip and it's a huge ski mecca.

http://www.whistlerblackcomb.com/index.htm