Symptoms

Which Framework Version should be configured in K2 host server configuration file (K2Server.config)?
 

Diagnoses

K2 documentation details how to change Framework Version in the following KB article - "How to change .NET Framework Versions"

But this KB does not elaborate on which version do you have to choose and when, mentioning that  normally you may want to change this if you getting the following error:

"This assembly is built by a runtime newer than the currently loaded runtime and cannot be loaded."

This is an error which occurs if a newer version of a DLL is used than what K2 expects.

The shortest answer would be too keep the default setting that K2 is installed with. The reasons why this might sometimes be changed is if a custom service broker or assembly reference (via assembly service broker or workflow) is compiled in a different version of .NET, or potentially any other custom code somewhere in K2. But if you are creating any new custom code then again you can just compile it against the K2 default framework version and have no need to change this. So this is usually only needed for customers with older installations with old DLLs that cannot be updated easily.
 

Resolution

Generally it is preferable to keep he default setting that K2 is installed with unless you have reasons to change it (see details above).