Drizzt- and Elminster-hatred aside (and man, must your DMs have been using these NPCs badly to warrant such ire; for heaven's sake, El is supposed to be the setting narrator!), setting change is what it's all about IMHO. While I agree with Moogle that it's important to maintain the continuity of the setting, IMHO that's just to make the PCs' accomplishments all the more important. PCs who want to destroy the Zhentarim should be able to deal major blows against the organization, given time and planning; they just shouldn't be able to pop around and obliterate Klauth, kill Manshoon, wipe out the Church of Cyric, and steal all of Larloch's magic before lunch. One of the nice things about FR is that it enables players to have their PCs effect major achievements and changes to aspects of the setting without causing any single campaign to utterly destabilize the setting. I've run several games in the Realms, and each leaves its own unique mark. However, the setting's still around for people to know and love.
So, in short, dreaded_beast, if your PCs can kill off all the beasties in Tilverton's sewers, let 'em. If they can gather the resources and magic required to storm Darkhold (and plan well enough that they can survive the massive wave of retribution that surely will follow), let 'em. If they can carve their way through Larloch and his spellweb of liches: Well, they're probably 40th+ level by then, so I can't really give advice on that. But the point is that FR is built to be a "big" campaign world (unlike Eberron, which is highly focused on the individual game at hand) specifically to endure such shocks and give the players the extra richness of transforming the setting that their characters, and others, will hopefully travel and experience for years to come.
(This, incidentally, is why I have a serious problem with the FR novels; it tends to cheapen the PCs' own actions vis-a-vis the setting to have a bunch of author-invented characters and spontaneous earth-shattering events transform the campaign world offstage.)