I have have two PVR250 tuners, one using a digital cable box controlled via a serial irblaster, and the other hooked directly to the analog cable line. I now have a second digital cable box, and would like to add it and control it with a second irblaster. The two boxes are the same model so they must have their own dedicated blaster, the computer has 2 serial ports available. My question is how should I edit my hardware.conf and irblasterd.conf files to make this work?

AFAIK, The lirc serial module only caters for a single blaster and only one instance of the module can be loaded. You may be able to get it to work following the instructions on the wiki, by having a normal lirc_serial instance as well as a ledxmit_serial instance.

Do your cable boxes have configurable remote codes?

I've been pondering a setup with multiple DirecTV boxes (one for recording / live TV, the other three dedicated to recording) but, if I understand what's been posted, it sounds like it would be a significant challenge (impossible?) to do so.

Is my assumption correct? Anyone made it work?

I certainly dont think it's impossible, it's just that LIRC is not set up to deal with that situation. I fully expect that the lirc_serial and ledxmit_serial instances would work.

A quick google turned up this where someone has taken a similar approach, but renamed it lirc2 and lirc_serial2 instead of ledxmit:
http://www.ozmyth.com/wiki/Configuring+ ... R+Blasters