It really depends on a few things.
1) Exchange 2000 or 5.5
2) Using SMTP, POP3 and IMAP?
3) Using OWA?
4) Is the server in a DMZ?
If you put a Exch 2000 server on a DMZ, you're looking at a world of headaches. It can be done, but it really negates the entire concept of a DMZ. You will need to open ports for things like Kerberos, LDAP, etc so that the Exchange box can communicate with the Active Directory.
I've had alot of success using an SMTP relay in a DMZ situation. It accepts mail in the DMZ on behalf of the Exchange server, located in the private network. It content checks and blocks spam, then passes it along. Works well and saves the headaces. Even the IIS SMTP server will do this well enough, just make sure it isnt an open relay.
If it's just behind a router, on the same network as a DC, then open 25 (SMTP) both ways to allow incoming/outgoing mail. Make sure it has a way to resolve internet names, and that it can be resolved on the internet itself. ( Map mail.yourdomain.com to the external ip of your router) That's the simplest way to do it.
Exchange uses SMTP by default, which is an RFC standard and non-propriatary. It can use POP3, IMAP, etc as well (most of which allow clients to retrieve mail only). SMTP is still used to send in this case.
The simplest way to do it is to use SMTP for everything.