The players encounter an organization dedicated to toppling tyrannous governments; both good and evil. Secretly, they are led by the twin daughters of Lucifer / The Lightbringer / (Generic Adversary God). These daughters have an appropriate set of divine or demonic powers, but strictly speaking, are not evil.
For you to have a near-death experience, Death must have a near-YOU experience. Take care to treat him well, and you may be rewarded... eventually.
The PCs are accosted in a major city containing at least one famous fortuneteller / prophet of the future. They are informed that their as-yet-unborn child will (insert terrible evil), and that, although they are very sorry, the PC must be executed to keep this from happening.
A terrible teleportation incident makes inter-demihuman chimaera of all the PCs. Quoth Master Adams: 'I teleported home one night / with Ron and Sid and Meg / Ron stole Meg's heart away / and I got Sidney's leg.'
Telepathically linked twins that have the ability to switch places. Literally. They've learned to exploit this 'tag-team' throughly.
What if some crazy wizard created an artifact that empowered rodents that touched it with one random supernatural power? Preferly right out of the pages of your favorite four-color. (But only one power!) This item does not convey any sort of intelligence boost.
Somewhere along the line, someone very powerful lost their marbles. Literally. Possessing a marble allows incredible clarity of thought about a particular related subject.
The old pantheon is dead, starved to death from lack of worship. If a powerful mortal can create a cycle of Faith, he can become a New God, to some limiting point.
Somehow, someway, a band of gnomes learns how to be ninjas. In fine gnomish style, they open an academy to teach this art to other gnomes. Wacky Hijinks ensue. Or the gnomes become some of the finest assassins in the land. Or both.
A massive iron key - 2’ length, 20lbs forged from the bones and horns of demon-lords. When used with a massive portal - carefully built according to documents found in powerful books of evil knowledge, it will open into the realm of demons and allow them to flood into the world. The applications of this item for villains are obvious. Mortals touching this item directly will suffer very dire consequences.