Unfamiliar to the Audience. Something that's unfamiliar to the reader is a little easier to wrap our heads around because it's based on our own experiences and limitations. I'm convinced that one of the things that made The Martian so successful with audiences is the fact that it made things that most of us know very little about (botany, space, and survival) and taught us about those things as we read along (or watched). By the end of the story, the audience knows a lot more about those three things than they started. Maybe not enough to survive stranded on an alien planet like Mark Watney did, but enough to know a little more about what to do in that situation than before. Or at least to be impressed with the logical progression that Mark Watney took to overcoming a seemingly insurmountable problem.

Unfamiliar to the Character. Something that's unfamiliar to the character can be a little tougher, because you have to walk a thin line between respecting what the character doesn't know and making sure the audience doesn't get too bored waiting for the character to catch up with where they are. A good example of something that's familiar to the audience but unfamiliar to the characters are procedural (like many James Patterson books) where the chapters alternate between what the villain is doing to further his plans and what the hero is doing to foil those plans. A bad example of this kind of narrative are those stories where the hero is stumbling through a series of dull hurdles while we yawn and wait for the hero to have a sudden realization or piece together a clue that's been staring us in the face for chapters and chapters.