Please note that I am also looking at 1374 DR, none of that stuff that happened in 4th Edition, I feel I must point that out because it would most likely be relevent in one's choice.
So...where in and around these areas would you be most likely to set up shop? Why? I would love to hear everyone's thoughts and reasoning on such a thing.
Sembia, Cormyr, and the Moonsea are all excellent if you had a political game in mind.
Cormyr has always been a hot-spot for political intrigue, shadowy alliances, and two-faced nobles scheming against the Crown and the common folk. The place is crawling with War Wizards, elite houses, and loyalists all looking for the aid of adventurers in either defending or working against the will of the Obarskyrs. Sembia is similar in terms to the number and layers of plots that are forever moving and shaking society, but Sembian schemes typically hinge on coin more often than Cormyr's. Politicians scheme against one another and use bribes and intimidation if need be, and the wealthy look for ways to take from their rivals and protect their own pockets.
The Moonsea is a different animal, in that it is various city-states vying for supremacy and brokering alliances to ward off potential enemies. There is a greater diversity of custom in the Moonsea, and backstabbing occurs on a grander scale. Betrayal and friendship can splinter and unite entire regions, depending on the plot.
What the Dales lack in political plots they make up for with good ol' fashioned ruins and wilderness. Forgotten crypts, monster-infested ruins, and ancient sources of magic are best placed in the Dalelands, especially considering the proximity of Myth Drannor, which is a wonderland of death traps and dangers assuming you stick with the pre-Return version. The Moonsea offers plenty in the way of roaming monsters and uncivilized perils, as well. Cormyr and Sembia are better patrolled, though; if the threat involves aiding an undermanned defense of a specific area, the Dales or Moonsea would work better. If you want to uproot a threat as a coordinated effort with an effective military, Cormyr or Sembia is probably better (although there are a few Moonsea cities that would fit the bill, too).
I'm also looking into what I am calling the "Skyrim Effect"...essentially while you have a main quest, you can literally stumble over smaller, quick run quests as well. This isn't something that I've done before, at least to the magnitude that I am thinking right now, but I want to give the players little things to do between point A and B. You know, "Bandits have stolen Ingrid's necklace that she got from her mother and retreated to their lair in the hills, and the constable is too busy with ensuring the safety of the rest of the town to chase them" kind of stuff. Not overly deadly or difficult sometimes, but some flavor and fluff, practice, if you will.
Overall, my main campaign idea stretches the length and breadth of Toril, an epic campaign that will take these players to places that none of us have been before, which involves months of planning on my part. Taking them to strange places, I want them to have a more familiar place to be able to return to when they need to, and that ranges from the Moonsea all the way to Waterdeep. Having played in these areas, they will encounter past characters that they've played as, a personal touch that I feel will enable them to make a deeper bond with the campaign as a whole. But just because they are familiar with the setting, doesn't mean I always want them comfortable.
Ultimately, I think I'm looking for an outside POV, maybe a observation that I hadn't seen yet concerning those areas. You've definitely given a fair amount of that thus far though, what would your personal preference be?
In your case, that would be good maps.
Frankly, what you are doing is much like I am doing with my current Neverwinter campaign. There is a larger overarching plot but lots of little side plots and locations for the PCs. Even the overarching plot has been driven by the active choice of the PCs.
One quick warning: you are talking about an enormous amount of prep. This being the case I would focus on those areas with the best maps - the North, Cormyr, the Dalelands, the Underdark - which, coincidentally, are also the areas where you're only a Google search away from some quick descriptions and adventure hooks.
What is your overarching plot idea, by the way?
I still have the 3rd edition Forgotten Realms sourcebook with the foldout map, plus some old 2nd edition maps as well. As for the overall plot, I've labeled it The Pillars of Creation for the moment, one of which is potentially in the High Forest. Still working out many of the details currently, but I am not planning on starting the campaign until September or so, thus I have plenty of time to work every out, as well as create a 'mini-quest' portfolio along with other odds and end.
If they survive, that is.
If you're looking to put politics off to the side for the time being, I'd recommend Arabel. Volo's Guide is written from the perspective of 1368 DR. But I can't imagine the region changes THAT much in 6 years (everyone should still be alive, simply 6 years older).
Arabel is good in that it's a "frontier" city. It's the one city in Cormyr where you don't need to keep your weapon peace bonded which makes it more forgiving to adventurers (although funnily enough you could have the gate guards insist weapons must be peace bonded when LEAVING the city, trapping the PCs in the city unless they have their weapons peace bonded or can get an exception). In order to be able to have your weapons not peace bonded in the rest of Cormyr you need to belong to an adventuring company (or have a writ from the King). This gives you an NPC that can provide the PCs with "a loan" to put up the startup money required to purchase an adventuring company license which allows you to steer the PCs towards certain adventure hooks while giving them the freedom to choose their own in other areas.
Arabel is also bordered by the Stonelands which is the perfect site for more traditional adventures while the city sees more than its fair share of traders, allowing the PCs to hire on as bodyguards should they desire to travel anywhere.