X-Files-esk campaign brainstorming needed!

If you'd prefer canon, however, just make it a Gehenna campaign. The 'loths are pretty Illuminati-like, and instead of FBI agents, the characters can simply be adventurers hired to solve a recent murder or something extremely simple, but end up entangled in a thick, tangled web of espionage, The Blood War, and intrigue. Though the big secret wouldn't necessarily be the Blood War thing. Maybe the 'loths have some elaborate plot towards overthrowing The Lady and taking over Sigil (maybe an artifact capable of destroying her)

Another idea instead is a chain of adventures I made seeds for but haven't posted here yet.

(14. An epidemic of half-elemental kidnappings has taken place over the past several years, among multiple races. Tracing it to its source, the PCs discover that the victims are "sacrificed" by being thrown (unbeknownst to the cultists) into portals leading to the lairs of the Princes of Elemental Evil, whereupon they become slaves or servants of the archomentals. The PCs also uncover the escalation of a plot for a vast breeding program between elementals and mortals to produce half-elemental progency.

(9. Cryonax seeks to collect the 999 fragments of Winter's Resurrection, an orb-shaped artifact of epic power used after the Law-Chaos war to end the long age of Fire that dominated since the beginning of the Permian analogue, and tipping the elemental balance from Fire and Earth to Air and Water, resulting in an ice age on most prime worlds. (it was so powerful that a single use shattered the vessel containing its power, scattering its fragments across the inner planes) Cryonax already possesses most of the shards, but has yet to collect the Chillsword from Magma (the Chillsword is an artifact forged from a tiny sliver of the orb, and has frozen a square mile radius of the plane), the one in possession by Yan-C-Bin, and finally, the one which fuels the glacier serving as Levistus's prison.
Since the completion of the orb requires that Levistus be freed, this adventure could have some interesting long-term reprecussions even if the players are successful in shattering the orb before Cryonax gets a chance to use it. (Glacial Inferno from Dungeon 103 may be used to build up to this adventure, as it involves a major artifact which could easily be a shard of the Winter's Resurrection. Of course, the concusion of the adventure would have to involve Cryonax's minions taking the shard, rather than it being destroyed, providing a sort of Deus-Ex-Machina for that adventure)

--The next adventure might possibly involve the ramifications of Levistus being freed. Alternatively, you might use this as the plot of an entire adventure path for the next batch of PCs your players create after retiring the current ones.

The climax: (8. The cult of the Elder Elemental Eye and the Doomdreamers are about to release Tharizdun from his prison. The players may have to enlist the help of Cryonax and Yan-C-Bin in order to stop such a disaster from occurring. (the Doomdreamers themselves are very secretive and are the hidden front behind the Cult of the Elder Elemental Eye)

The cult of The Eye, the Scarlet Brotherhood, and even the Doomdreamers could provide background noise until scenario #8 (in all likelihood the link bet. 9, --, and 8 is that Doomdreamers and the Scarlet Brotherhood played a hand in attempting to get Levistus freed, and were also involved in making sure that Cryonax succeeds in reforging the Winter's Resurrection.)

Back to the Yugoloth campaign, you could alternatively start with Inner Planar adventure seed # 17, as there are aquatic species of Yugoloth on the Elemental Plane of Water (it's a bit silly, though)
(17. A beer spill of epic proportions in Sigil forces the PCs and NPCs to open a huge one-way gate into the Paraelemental Plane of Ooze in order to empty the deadly torrent. However, due to some miscalculations, they accidentally open a portal to Elemental Water instead, earning the wrath of the Padisha of the Marid, Ben-Hadar, Blibdoolpoolp, and several other big names of the plane.

While I don't have any specific plot ideas to suggest, I would definitely suggest involving the Keepers somehow. They're perfect for an X-Files-esque game; they're mysterious, otherworldly, there's a big conspiracy around them, the "government" (the Guvners) is involved in their existence. They even have sort of a Man-In-Black look to them.

At the heart of the main story behind the X-Files is a conspiracy, so you need something sufficiently significant to fuel said conspiracy.

Well, the Tharizdun/Inner planes campaign seeds I mentioned would fit that, as would the whole Yugoloth thing. The Yugoloth thing could actually climax with a physical encounter with the General of Gehenna (I always imagined him as being surrounded by a pall of shadow to diurnal creatures, appearing as an indistinct silhouette, while to nocturnal and light-sensitive creatures, he appears as a bright being surrounded by a corona, with the luminousness of his body giving him an indistinct appearance) The PCs (assuming this climax doesn't occur at 20th level) are henceforth hunted by the 'loths and their minions since they've enjoyed a glimpse at the Yugoloth patriarch.

While your campaign has whatever rules for the planes you want, canonically it's only planar towns and regions that shift around like that.

There were? I honestly don't remember that offhand, where an entire world was sucked in. What was that, out of curiosity?

^^Yeah, I believe that's it.. or maybe it was Expedition to the Demonweb Pits.... At any rate, even that tidbit was reprinted and updated from the Queen of Spiders trilogy from 1E. I'm pretty sure there's also a 3x book or Dragon/Dungeon issue that also mentions Orcus attempting such a thing with either a city or prime world, but failed.