I worked on Mysteries of the Moonsea, so I might as well chime in.
First of all, this isn't the first time that people have predicted the death of the regional sourcebook, and I strongly suspect that it won't be the last. To the best of my knowledge, WotC has no intention of permanently changing the format of the regional sourcebook into something like Mysteries of the Moonsea.
In my experience, a "Mysteries" book usually presents, well, mysteries - locations, events, and denizens that don't normally make the map. We did one called Mysteries of Arena for Oathbound, which wasn't entirely dissimilar to Mysteries of the Moonsea. In other words, I don't think it's really accurate to lump Mysteries of the Moonsea in with regional sourcebooks.
I also think it's safe to say that there is so much 2E material out there about the Moonsea, that perhapse someone at WotC assumed that the real FR fans would already have Cloak and Dager, and the Moonsea suplement from 2E. In that respect, other than the rebuilding of Zhentil Keep and a few minor changes, there isn't that much change there, so it's the perfect location to try out another type of book. At least I'm assuming that has to be the thoughts running through the heads of the people who outlined the thing. I don't know for sure, but it makes sense to me.
While I was working on it, I actually equated it more to Ruins of Adventure (or Pool of Radiance). It details a few major locations and then a bunch of linked adventures related to that location. The only thing it lacks is a major villain or storyline linking them all together. The thing is that in the Forgotten Realms, I don't see it being particularly difficult to come up with the major plotline linking all of these adventures on your own.
Anyway, that's my take on it. I would certainly not rate it as my favorite regional sourcebook either, but that's because I don't really think it fits the category. And for those who voted Serpent Kingdoms as their favorite.... umm.... thanks!