Hint: it isn't ISA
We recently moved to a new set of IP addresses and a new router and while most everything was running fine our Edge Server was having trouble sending/receiving from the world at large.
Now I have the Edge in a DMZ in order to use a public address since ISA does not doing client NATing at all (curse you!) and initially I suspect there was something in my subnetting or some such that was the problem. Maybe it was the "Perimeter" network object that was the issue? Could it be something whacky with my ruleset?
However, I was able to connect from our hub server to the edge server (ie from in to out). I was able to connect back to the hub server. I could even get out from the hub server (using the default NAT address). I just could not get OUT from the edge server. No DNS lookup (using outside), no web browsing, and definitely no SMTP happening here...
I kept going over and over looking for what I had configured wrong on ISA or on the Edge server or in DNS...
So I enabled pinging on the ISA server for all Networks so I could check and sure enough, while I could ping the "External" Nic's ip addresses from the router, I could not ping the DMZ Nic, much less the Edge server on the other side of it.
There was no route manually specified for the particular IP address that the Edge server was running. DOH!!!! A wee bit o cisco magic and *voila* email flowing like there is no tomorrow.
Assumptions, assumptions, assumptions...