Where did that come from?

Enough aliens

Enough vampires

Enough government conspiracies, mind-capturing computer games, secret organizations and parallel dimensions.

It's been said for television that a show passes its peak once it resorts to the evil twin episode. And there are plenty more concepts just as contrived that will wreck the suspension of disbelief, confuse the audience, punch holes in the plot (or just announce that the writer had a slow month).

There are a number of good webcomics out there which jam a nonsensical plot line into an otherwise good story. None of the above topics are inherently bad (well, I might have to revoke that on the computer games one. Characters physically entering the computer games they play is pretty hokey no matter what), you can tell a good story about vampires or dimension hopping. The trouble comes when they're stuck into a setting that can't support them.

For better or worse, the opening story lines define the strip. Stray too far and the plot loses its flow. Once you establish the plot as being something down to earth, introducing a large mass of fantasy elements will be confusing and disruptive. Interrupting a story based on a supernatural plot with mundane matters has a similar effect. It's fine to surprize the reader with the plots direction, but tearing up the basis built up from the beginning goes too far.

Gradually easing new concepts doesn't always work. In some cases, you're left with a clumsy feel to the plot (such as when a character dabbles in some field which suddenly becomes central to the next arc). It's slightly more palatable moving from supernatural to pedestrian. We can imagine the characters have a life beyond what is seen, and if it's casually brought up a few times it becomes part of the flow.

If an idea just has to be used, there's nothing wrong with taking a break and starting a new setting. As the main story gets more predictable, a quick context switch can be refreshing. Once established, settings can draw off the ideas best suited to them. Or, the story can adapt to fit the setting. How many times has Hamlet been rewritten?