The proverbial 800-lbs. gorilla in the room when talking about threatening Earth impacts has up till now been the spectre of someday finding a massive long-period comet nucleus (with consequent very high relative velocity with respect to our planet) on a direct collision course. Although the probability of such an event occurring within the next tens of thousands of years is apparently quite small, it is nevertheless non-zero, and therefore merits discussion.
On the face of it, there seem to be few conceivable countermeasures. The entire known world nuclear arsenal would not provide enough energy to positively deflect such an object during terminal approach (defined here as the perhelion phase of its orbit, within the orbit of Jupiter), even if the required delivery systems were immediately available. Furthermore, mere fragmentation of an impactor may not significantly decrease the negative effects of impact. However, such a brute-force approach may not be the most effective strategy.
The various NEO watch projects have amply illustrated the fact that orbital uncertainty is the norm for even small, inert objects whose orbits are confined to the inner Solar System. Long-period comets are observed to have large reservoirs of volatile materials; why not exploit this feature to alter their orbits as needed?
I propose a systemic approach to mitigating this risk. New "Spacewatch" programs designed to detect long-period comets years or decades from entering the main Solar System are central to threat mitigation; such searches would also serendipitously detect many KBOs. Obviously, we also need to develop a much better understanding of the composition & mechanical properties of comet nuclei in order to formulate impact countermeasures. Results from Stardust thus far may indicate that comets are more heterogeneous than originally assumed, but Wild-2 may not be typical; similar missions should be performed on several long-period objects in order to obtain more representative data.
The end result, if pragmatically useful, would be a network (at least three stations) of ready interceptors appropriately positioned along Jupiter's orbit. These interceptors would be nothing more than high-mass impactors with the capability of intercepting comets at the greatest possible distance from the Sun and striking them while still many years away from perhelion in order to expose volatiles to solar heating as early as possible, resulting in sufficient outgassing to alter the object's orbit away from an Earth collision trajectory. In all likelihood, any orbital change if accomplished far enough away from perhelion would be enough to prevent a catastrophic collision, even if the Moon & Mars are factored in as colony sites a few hundred years from now.
Okay, now I'm gonna drink some more beer. Happy New Year, everyone!