Things That Go Bump in the Night
The Universe is well populated with catastrophic hazards. Wandering black holes, supernovae, gamma-ray bursters, intergalactic collisions that spray a whole galaxy with radiation, not to mention the more prosaic collision with an asteroid.
One thing these have in common is that there isn't anything we can do about them - though in a few decades we might be able to deal with a wandering comet or asteroid that has our number, if it announces itself well in advance.
UPDATE: Bee has some thoughts. See link at Blogroll.
On the other hand, there are the disaster we bring on ourselves. Most of the common epidemic diseases that plagued us for thousands of years - measeles, smallpox, etc., we got from the animals we domesticated. Even the modern scourge of AIDS was contracted from monkees. We also have a bad habit of devastating the ecosystem. The Native American immigrants to America of 13000 years ago promptly killed off a lot of the big game - elephants, camels, giant beaver, horses. Gun wielding Europeans came close to finishing off the rest.
More modern adventures are there too. Asbestos mining practically wiped out the small town of Libby Montana. The toxic stuff not only killed the miners, but the dust on their clothing also devasted their spouses and children. The clean living Mormons of Utah have very high cancer rates thanks to nuclear testing in Nevada, and everyone in the world of my age carries around some of the fallout in our bones.
One big challenge we face now is the threat of anthropogenic global warming. Unlike some of the others, we can't say that nobody saw this one coming. It doesn't seem likely that it can be prevented though. I see very little appetite for the kind of sacrifice likely to be required.
AGW is probably only a civilization destroyer in its worst case manifestation, though. How about more drastic stuff?
One of the odd puzzles of our Universe is apparent absence of other technological civilizations. "Where are they"?, as Fermi asked. As we have learned about star formation and planetary formation it has become obvious that planets are commonplace, as are stars like the Sun. What little we know about the origin of life argues that it too is likely to be common. As we run out of excuses for the absence of aliens to greet us, one ugly possibility rears its head.
Maybe when a civilization reaches sufficient technological maturity to advance to space it manages to destroy itself. Just about the time it starts getting decent space legs, it's probably also starting to probe the weak interaction center, thereby producing something bad, like a strangelet or a black hole.
Personally I think we face a much greater threat from Lord Voldemort. Not to mention George Bush.