I think a PO box might have at least some agents wondering, unless you live in the boonies and say so in your cover letter.
If you don't have, or don't want to use a street address, perhaps you can rent a box from one of those Printing/Courier/Copy joints that seem to be springing up all over. There's even one in my little town. It used to be called Mailboxes Etc. but changed its name recently to something else (forget what).
I know they advertised that although it's a box rental, your mail is sent to a street address and no PO# appears in the address. They may or may not sign for packages - I have no idea.
I don't know how often an agent would send anything via FedEx but publishers sure do, so if you're looking that far down the road, you might want to try to avoid using a PO box.