One of the things discussed in the development of 5e is that we're now in a world where most people's primary fantasy touchstone is no longer "Lord of the Rings", but rather "Game of Thrones". This means that the expectations people will bring to the game table are likely quite different, and also means that what people are looking for from the game are also probably different.
While D&D is not "Game of Thrones", any more than it ever was "Lord of the Rings", I do wonder to what extent that should perhaps influence the game?
Humans Only: It's an interesting fact that Gygax actually wasn't a huge fan of "Lord of the Rings". He actually preferred the stories of Conan, Fafhrd and the Grey Mouser, Elric, and the works of Lovecraft. In fact, I suspect he would have omitted the 'demihuman' races (as they were then known) entirely, except that the player base expected to see them.
However, in the post-GoT world, I wonder if it isn't time to significantly re-evaluate whether the non-human races should be de-emphasised, or even eliminated? I have two reasons for this. One of these is that GoT probably has deeper characterisation than has been the norm in fantasy stories. Meanwhile, in D&D it is sadly not uncommon for players to use their character's race as a substitute for character - they're playing "the elf", and that's enough.
The second reason for this is that an awful lot of the character work in GoT deals with several inter-related houses of nobles in the setting: the Starks, Lannisters, Greyjoys, Boltons, etc - and note that the inter-related nature of those houses is often fairly crucial to the plot. But where the 'houses' are replaced with different species you lose those inter-relations. Which means the setting then either needs to duplicate the setup several times for each species in turn, or it loses a key chunk of the campaign.
Low Fantasy: A long time ago, some bright spark drew a distinction between 'high' fantasy such as the King Arthur myth, Lord of the Rings, and the like; and 'low' fantasy like the Lankhmar stories, the Black Company stories, and Game of Thrones - settings that, while distinctly fantasy, tend to deal with human-scale issues. While magic, and even quite powerful magic, does exist in GoT, it does tend to be fairly rare and fairly subtle.
D&D has always had a somewhat tricky relationship with those two influences - the level structure tends to mean that characters deal with low fantasy issues at low levels but then 'graduate' to high fantasy at higher level (with the switch-over point moving down with each successive edition - in 1st Ed it was around level 10; in 5e it's closer to level 5).
(But, on the other hand, while D&D is now in the post-GoT world, it's also in the post-Harry Potter world, so maybe this is a case where the game should embrace that side of the equation?)
Mature Themes: Tricky one this - in D&D, "mature themes" has only really appeared in a couple of official products (3e's "Book of Vile Darkness" and "Book of Exalted Deeds"), where it more or less boiled down to "boobs and blood". "Game of Thrones", of course, isn't exactly short of boobs and blood. On the other hand, though, there's rather more to it than that - there's all manner of shades of grey, deals and betrayals, and characters who go from heroic to deeply flawed to back again.
So what does all that mean?
I'm actually inclined to wonder whether WotC would be well-served to bring back the short-lived "Birthright" setting. Though if they were inclined to do so, I'd suggest that they don't simply reprint and/or update the setting, but instead re-imagine the setting in light of the post-GoT world. And, in particular, they might be well-served adopting both the human-centric and mature themes elements - I do think there's potential for them to do extremely well if that were done.
In terms of my own table, though, it doesn't mean too much will change... for now. I am pondering the possibilities of homebrewing an entirely new setting, as I'm no longer convinced 5e does Eberron terribly well and I'm not a fan of FR, in which case I'll probably adopt some of my thoughts here. But it's really early days at this stage.