The Pestilence, an illness that swept across Equestria decades ago, killing everything in its path.
First it killed the plants, then it killed the animals, then it started killing us.

To escape from the disease below, the ponies left created magical floating islands, pieces of Equestria that could be separated from the earth below before The Pestilence could infect it.

Apple Bloom and her family lived upon a floating farm, their land was safe from disease, although they weren't.
The pestilence is still capable to spreading to ponies, although it happened somewhat rarely, especially compared to how common infection was on the ground.

This is a young, yet independent filly's journey across Equestria to save herself from illness.