These are what we call the 'YMMV items.' Things that some people find in this work. We call them 'your mileage might vary' because not everyone sees these things in the same way. This starts discussions in the trope lists, a thing we don't want. Please use the discussion page if you'd like to discuss any of these items.
Creator Worship: Many of the more rabid fans believe Randall has the ability to read minds and they often try to emulate the wacky antics depicted in the comic. (Of course, that's usually because it sounds like fun, not because the master has spoken.)
"Funny Aneurysm" Moment: This strip is perhaps the fastest example of the trope happening in recent memory. (For the record, just days after the strip was put online, no less than twelve tornadoes touched down around the Dallas metropolitan area, causing quite a bit of damage.)
Strip 527 jokes about how Steve Jobs was losing weight. This was made before it was known he had cancer, let alone before he died.
453's alt text: "I'd like to see more damage assessments for hurricanes hitting New York and flooding Manhattan — something like the 1938 Long Island Express, but aimed a bit more to the west. It's just a matter of time." Enter Hurricane Sandy.
Gateway Series: xkcd has gotten a lot of people into webcomics in general.
Comic 1190, "Time": Each frame is the size of a full comic, and rather than posting them all at once, the page updates every hour with a new frame. This has been going on continuously since March 25, 2013, with no end in sight. With over a thousand frames long, it has become a separate webcomic within a webcomic!
Lanes. Treating cancer leaves a 40% chance that it will recur somewhere else in the body. "So you spend the next five or ten years trying not to worry that every ache and pain is the answer to the question 'Do I make it?'"
An In-Universe example: Core: "I freak out about fifteen minutes into reading about the Earth's core when I suddenly realize it's right under me."