Wow, after all this time I finally make a post...
The number one threat to the Imperium is itself, plain and simple..
First, disregard all of the OTHER reasons why the Imperium is dangerous, like religion, fanatacism, complete disregard for life, etc. and look only at what a directed Imperium can do.
With the Emperor at the wheel, how quickly did the Crusade advance? Yes, many of the worlds that joined were already settled and home to mankind, but just as many, if not more, were openly hostile to the idea, thus, many wars. Even with all that, it took the Crusade what, three hundred years to claim most of the known galaxy? Yes, Maccarius cut a swath through parts and there have been subsequent conquests and expansions, but nothing even comes close to the original, especially since much of what Maccarius claimed was actually retaking worlds that had been claimed then lost during the Heresey.
So let's say that the original Crusade took, oh, 75% of the galaxy in 300 years. If anyone has the specific numbers, let me know. Still, going off that base figure, that's a lot of conquest. That means dozens, maybe hundreds, of worlds every single year were conquered by the Imperium. How long does it take for a hive fleet to strip a single world bare and move on?
So we now have to imagine that massive amount of war effort, but without a purpose. The High Lords are there, yes, but they each have their own agenda, as do the various lord-generals, planetary rulers, and such. Thus, you now have an even larger military force, but without a single, motivated leader; instead it is fractured and pulled by various special interests. The greatest military force in the Galaxy (yes, bigger than Orks, for a number of reasons) is now left to sit and wait. The fringes suffer and are on constant alert, like Cadia, but the interior is insulated against external threats - thus, any and all threats they experience are internal, a byproduct of this new-found idleness. An occasional Xenos raid or natural event happens, but the vast majority of evil wrought on these inner worlds is a product of Men - be they cultists (Could be an argument for Chaos, but I prefer the idea of human weakness) or simply egotistical nobles, they're still men, by and large.
The next big question is whether or not there are any external threats that can match or exceed the threat that Man poses to himself and, more importantly, whether or not they could stop a directed Imperium.
Tau - Even with all their technology, the Tau, at the moment, are nothing compared to the Imperium. They number only a few hundred worlds; compare that to the military output of the 1,000,000+ worlds of the Imperium. That means each Tau unit would need to be able to destroy at least a couple THOUSAND of their Imperial counterparts to be on equal terms.
Tyranids - Once again, how long does it take for a hive fleet to finish with a world and move on? Yes, they get stronger with every world they eat, but by destroying their food supply (ie a world they just fought for) they can be weakened. This is disregarding the fact that their nautical units are lacking in the long-range dept. and that a co-ordinated offensive of bombardment cannons would suffer few, if any, casualties while destroying a hive fleet.
Necrons - It took them thousands of years to even get a draw out of the Slann for control of the Galaxy. Plus, they're currently just waking up. A systematic offensive would wipe them out, especially if combined with a renewed scientific R&D.
Chaos - I point you to the Heresy, when they had almost half the Imperium under their sway, and they still lost. Today, it wouldn't even be a contest.
Orks - Interestingly, they're much like the Imperium - their own worst enemy. but unlike the Imperium, they will never combine under a single massive banner like Man does. Old Ghaz might have got a good Waaagh going, but even with superior numbers, he couldn't win. While full-scale elimination might not be feasable (at the moment) their numbers can at least be controlled.
... And with that, I'm off to bed. Give me a bit of time, and we'll see what else I can come up with.