The clock is ticking. The 5125-year-long cycle in the Mesoamerican Long Count calendar comes to an end on Friday, December 12th 2012 and as long as you don't account for the vagrancies of reconciling a stone age South American calendar system with 16th century Gregorian 'western' calendar and concepts like Leap Days, the world is either supposed to end or a long-dead civilization puts a “1” in front of all the dates on their checks (though it's likely to take 250 years or so before they remember to do it consistently).
So, say we are all on our way out, the real speculation is how we’re going to go. Earthquakes? Meteor Strike? Polar Inversion? Good, everyone's seen those movies, how about we look for a few armageddons that may have flown under the radar and see if we can find one that will send us out with a bang.
Eaten By A Giant Space Worm
Yes, the whole of the planet Earth, swallowed in a single gulp that would cause Galactus to need the Heimlich Maneuver. That was threat posed by Parasitis, a creature of unknown origin but of cosmic scale to the planet Abadox, a threat only countered in that fine video game tradition by a single man in a space fighter. If he can navigate this side scrolling shooter he can not only save his world, but a princess as well, that's a good bonus.
On 12/21/12: Tidal implications of such a creature nearing Earth aside, the fact that it can traverse the great gulf of the universe at all means that it can move at terrific speeds. That means no one on the facing side would get the view of massive teeth opening in the sky, everything would probably just go dark right away after the sun is blocked off, and since the Earth would basically be krill to Parasitis, humanity would freeze to death rather than been chewed.
Vaporized To Make Way For An Interstellar Bypass
The Hitchhiker's Guide to the Galaxy (1978)
Nobody likes traffic, even when you can move freely in three dimensions like in space, so when there is a planet in the way of galactic progress, the Vogons are contracted to clear the path in the kind of orderly and effective manner their people are known for. It's not their fault that the local population of humans didn't get the memo about it, after all the dolphins did and they didn't even have digital watches.
On 12/21/12: It's finally revealed that Mesoamerican Long Count calendar was in fact our official notice of the date and time the demolition. It's not the Vogon's fault that the Mayans were wiped out and the true meaning lost. When the Vogon constructor fleet arrives, they will be perfectly justified in their actions, after all we were warned.
Cat's Cradle (1963)
A testament to the power of ideas and the terrible implications as to what can happen when the really, really bad get loose. A metaphor for the atomic bomb, Ice-9, is a form of room temperature ice crystal that immediately duplicates its solid properties onto any moisture it comes in contact with. This, as the novel shows, includes plants, animals (like humans) or even all the water in the world's oceans.
On 12/21/12: If some Ice-9 were invented and got loose, or it spontaneously generated itself via cosmic radioactivity or some such, in mere moments all the water in the world would solidify. Those people not in contact with water in that moment would survive just long enough to accidentally ingest it and “freeze” or ultimately expire from dehydration.
Solar Flare Signals the End
Assassin's Creed Series (2007)
At the intersection of a star's plasma and electromagnetic energy there can be what's called a solar flare, a burst of solar martial out into the universe with the force equivalent of many millions of tons of high explosive. These brilliant displays have fascinated scientists and served as the desktop wallpapers for a generation of PC users. The ancient race that evolved first on Earth once put their considerable knowledge and technical expertise towards countering a massive flare that threatened them. They failed and it ultimately wiped them out.
On 12/21/12: It's easy to forget that this is the Sun's system and we just live here. If it were to contract a bad case of cosmic gas, scientists say we'd get about eight to fifteen minutes warning that a flare and its burning hot radioactive materials was on its way. The blast, if it didn't just vaporize the planet, would cause a nuclear winter style mass extinction scenario.
Extra-Galactic Composite Superlaser Strike
Star Wars (1977)
They had to test the thing at some point, right? There is no way you build a gigantic laser and then plan to advertise it as a planet killing weapon of terror that will keep the local systems in line if you are not absolutely sure the thing is going to work. So, at some point the engineers of Galactic Empire got all the lenses aligned, all the plugs plugged in, retreated to an extraordinarily safe distance behind the thickest pane of Lexan glass in the universe and pulled the trigger on the bugger. Just to be safe, of course, they fired out into empty space.
On 12/21/12: What if that event happened a long time ago in a galaxy far, far away? Sure the laser would lose some of its potency as traversed the great distances of the void, but since it is a superlaser with incredible destructive power, there'd be a blinding flash of light, then boom. The only real question is if we'd make a big enough ripple in The Force and if there would be anyone left who could feel it.