To continue your VM and hypervisor analogy, there is a class of hacks in which virtualized software breaks out of the VM and is able to observe and/or mannipulate host. For example, http://www.theregister.co.uk/2008/02/25/vmware_critical_vuln...
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Moreover, even without breaking out, it is -- in some cases, at least -- possible to detect presence of hypervisor by carefully timing computations. Albeit those methods seem to depend on access to a timing source that is reliable (i.e., outside of hypervisor's control). For example, http://www.cs.cmu.edu/~jfrankli/book_chapters/virtual_machin...
See my other comment about Kant: http://news.ycombinator.com/item?id=3932514
For the general case of virtualization, breaking out of the simulation would be as impossible for us as it would be for a video game character.
If we could find a cosmic equivalent to plug into the universe we might just be able to determine whether we're in a real or virtual one after all.