If I have email subscribers who had opted out at one time, but then visit my email preference center and opts back into receiving emails, is Marketo smart enough to opt them back in or do I need to create a smart campaign to specifically opt them back in to remove them from unsubscribe?
If you do not set the system Unsubcribed field to true it will not be set automatically.
It doesn't need to be done in a Smart List -- it can be done on the form itself, of course -- but it must be done.
So if I have a smart campaign that says: if "fills out form" and selects to "opt-in" via box selection (that's my "true") - then Marketo will take a previous unsubscribe person and resubscribe them to my email list?
Sounds like you're mightily overthinking this.
You must have a Change Data Value flow step for the system (native Marketo) Unsubscribed field if you want to change that field in a Smart Campaign.
No manipulation of custom fields (for example, fields you may use to opt in/out of various newsletters) will ever automatically change Unsubscribed.