One thing that always comes to my mind in this context is support for MS Windows VMs. While Qubes Windows Tools for Qubes R4.0 is quite satisfactory, the current state for R4.1 still has some deficiencies, so the migration from a Windows environment to Qubes R4.1 is not yet possible. And Windows users desperately need a way to move from this system to a real OS!
For the current state, see e.g. Testing Windows and QWT in R4.1.
Any help would be greatly appreciated.