I’d opt for straight through. Just do it.
Here are some things to help your trip:
*If you can afford it, try the new kid’ carryone luggage: Trunki, Skoot Kids, Kiddee Cases. Your child can sit on it as you pull it through the airport.
*Plan your flight in 15 minute slots - magazines, a favorite story book, drawing, snacks, etc. (and sleep!)
*Use a DVD player or tablet
*Your trip is a long one, but try giving them a little present every 15 min. to half hour of good behavior
*Stickers – decorate an empty water bottle or whatever presents itself
*Take a pillow – to sleep on or to sit on
*Lollipop – for takeoff, to help with any ear problems
*Sweets in moderation – raisins, other fruit

Potty trained or still in diapers?

Yes, direct! And IMO a car seat is more trouble that it's worth. The CARES harness is great at that age, though.

I've flown D.C. to Seattle 5 times with my now-4yo, and twice with him and my now-12mo. I've only ever done direct flights. It's a long enough day as is without adding extra flights, layovers, etc. At age 2, I loved bringing the car seat. I rolled it through the airport with my kid in it, and he sat in it through a lot of the flight.

There are tons of great threads with ideas for ways to entertain kids on flights. At that age, I tended toward snacks and reusable sticker books.

No layover. Direct. Ipad. Snacks. I think 2 is too big for the car seat personally. She will not want to sit in it.

Direct flight but there are only a few direct flights from here. Get it done. Bring car seat and iPad or kindle and lots of snacks and make it work.

She's only flown once (when she was 10 months) on a direct flight to Florida, and that was relatively painless. But she'll be two in a week and I'm booking a flight to Seattle in March. And, well, general two-ishness makes me a little nervous to fly such a long distance. Parents of active toddlers who have flown- is it better to just do a direct flight and get it out of the way (about 6 hours direct to Seattle) or pick a flight with a layover? Looks like there's a handful of direct flights but also a few that stop in Minneapolis or Detroit for 1.5-2 hours...so we'd do the 2-3 hours to one of those, layover, and then 3-4 to Seattle. Thoughts?