Do you have a super huge need for internal storage? The transfer speeds you get from ThunderBolt external drives means that there is little to no difference between external and internal. I have a 5 bay Drobo and a LaCie duel disk daisy chained to my MacBook pro TB port and I never worry about speed or space.
That's a very interesting question... I'd attempted at one point a couple years back keeping my iTunes library (a couple TB of movies, TV series, and music) on an external disk, but it just ended up causing endless problems, and iTunes freaked out a couple times, and refused to acknowledge the external library's existence, so I had to blow a half-day re-importing everything into iTunes, etc.
This experience is what pushed me towards my SSD+HD internal home-Fusion rig - and it's performed like a champ ever since.
I've also had challenges with external TB drives not waking, or sleeping, or connecting as-expected - I tried using an SSD in a TB enclosure as my startup drive for a while, with a an external 2TB HD as my bulk data drive, and it just never worked right at all.
To be fair, all of that was when TB was a new technology, and with first-generation TB enclosures, etc. It's totally possible that the tech has gotten better, and an internal SSD with external HD that iTunes, Photos, etc. point to will work better than it used to.
However, given that I'm committing to that plan when I buy an iMac (or going with the 3TB+128SSD Fusion option), for the life of the machine, I'm a little gun shy. If I buy it with just the 256GB SSD, then I'm on the hook for making it work, whether I'm attempting a home-Fusion with an external drive, or just pointing iTunes, Photos, etc towards external libraries.