And to balance Shemeskas post out a bit: while the setting has changed and the number of gods may finally have actually fallen into two-digit numbers, its still the same old Realms you knew - but 100 years into the future. Approach it like the old "Arcane Age" setting that presented Netheril as a playable place - another point in the timeline you can explore and have fun in.
The continuity from
3e is pretty strong, and there are a lot of cool ideas included: like earthmotes, flying little earth-islands drifting through the sky, Comyrs imperial ambitions, the Red Wizards as exiles trying to clobber together a merchant empire etc.
Its ideal for a new campaign. Happy gaming!