i'm looking at building a 4 axis cnc mill. can mach 2 or mach 3 handle the requirements of the 4th axis?

Yup, up to 6 axis.

Can it be used for differently configured 5 and 6 axis setups ?
Some of systems with # of axis >4 sometime are configured differently, i guess that probably is a question for the g-code conversion software used.

You can set up different configurations and choose them when you start the software, or set up an icon for each config.