Are they hard to maneuver, park, drive, navigating gas stations etc?
They can be more challenging than a motorhome depending on the size. Fueling up can be a little bit of a challenge with a long, 40' trailer, unless you just stop at larger truck stops. But are do-able without too much foofaraw.
If I get something like an f250 diesel, what would mileage be?
Of course it is dependent on your driving style, speed of travel, size of 5th wheel, but pretty easy to figure around 10 mpg.
How are grades navigated?
Just like anything: if you're big and heavy you'll likely be slower than the surrounding traffic. No Biggie.
what's set up like?
Not much different than a motorhome. Electric, water, sewer, etc. Quite a few new fifth wheels now come with auto leveling which makes setup easier I would imagine.
How hard is it to break camp and travel?
See above.
Quality is always suspect but what are the standard issues?
Poor construction is always an issue. Sloppy joinings, poor fit of cabinets, poor caulking, cheaper materials. More expensive 5th wheels don't guarantee there will be no issues, but do tend to have better materials. Due diligence, and a thorough PDI are absolute necessities.
Care/maintenance?
Thorough inspections of the roof and wheels/axles periodically. Normal vehicle maintenance of the tow vehicle. A close watch for any water intrusion.
DW worries about them flipping over and taking the truck with it in an accident, wind or uneven terrain. is that risk real?
Sure, if you search out YouTube videos you'll find graphic evidence that even semis can be blown over by the wind. Now, it's real, but unless you knowingly drive into severe weather conditions, you're unlikely to have it happen. Some parts of the country have very high winds as a normal occurrence. But if you're watchful, and travel with your eyes open, it is very unlikely to ever be a problem.