Hi Jamie -
We have 14 different business units in our global instance. We heavily rely on the Group functionality to do this. Every business unit is a separate group in Workfront and that has worked out great for us especially with the custom status options Workfront now offers.
For Companies, we use "Networks" as some of our business units cross report (i.e. we have 8 healthcare/pharma business units that all report into the same President). Since the Supervisor/Manager field can only be someone in the same company, we needed to do this so we could have the org chart we needed. This took a lot of thinking and we might have over combined/merged for some, but it was okay because security things are all based on groups.
Each group can have it's own Portfolios, programs, custom forms, and schedules. As an admin, I do use a grouping of Owner's Home Group Name (which you will need to do with text mode) a lot as different business units might have the same client so there will be portfolios with the same name and I have to make sure I'm looking at the right one.
This way does take some planning and there was one time we had to reconfigure because we didn't plan too well, but other than that it has been smooth sailing for the last 4 years. :)