slight RttToEE spoliers.
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I just finished running RttToEE in the Realms. My previous exposure to the realms before this came from reading everything by RA Salvatore plus about 10 other realms novels by other authors and playing icewind dale and Neverwinter Nights. My players all have various experience with the setting ranging from none to slightly less than me.
What attracted me to the Relams was the fact that everytime I set down to create a homebrew world it ended up looking 90% like the realms so I finally decided that it would be easier to fit my own original creations into the realms than the other way around. The other thing that attracted me was the fact that several of my player were sort of familiar with the setting. So when a player decided he character was from Badur's Gate, he kew what he was talking about. I also like the fact that if the players suddenly decide to go to "X" for any reason, I can quickly reference the FRCS and decide what's there.
So in my RttToEE campaign, the PCs spent much of their time in the middle of know where in the Western heartlands [which is were I put Hommlet and the major dungeon of the adventure]. None of the this was particularly tied to the realms but when the player found a power evil artifact in the course of the adventure they thought "Where do we take this?" They came up with Waterdeep, teleported there and I referenced the FRCS to see who it would make since to talk to. When they met Khleben Blackstaff, it didn't seem cheesey because he didn't introduce himself and only one player recognized the character. There have been several other situations like this one.
So, um....in short ...what jester said...