Any ideas on how to do this?  A plug-in?  I want to make the boxes fill the screen but have the ability to move them into different configurations (sometimes with one bigger image in the midde and the small boxes around the outside).  They will be on a colored background with small equi-distant space / borders between them.

It may be possible to do this in Media Composer, but you may find it far less frustrating to use After Effects.

You will find the 64 video track limit a bit of a complication if you do this in media Composer, although a bit of nesting will solve that. Whatever you do this in, there'll be a lot of number crunching involved to make the different layouts.