The thing I found, and which was actually covered in the manual, was that you need to tweak patches for each use.
Line 6 was really good about this and talked about it really early on. Additionally some very easy logic had to be assumed; the cab simulation is going to add or detract some things and when you use an actual cab it's an entirely different world and you need to take that into consideration.
I was in a pinch and ran my PodXT through a Crate PowerBlock and a Marshall 2 x 12 cab. I had about two days to pull it together before the audition and it took a little tweaking. In the end I found that I was best served by copying the patch, removing the Cab Sim, setting the unit for the proper output and then all that was required was a little EQing and probably a slight drop in the Drive. As a defined process I could see this happening pretty easily with most patches I would need through that rig.
I put together three patches, the one I used the most was a Marshall Plexi patch and that tone just killed! It really gave the other guitar player a run for his money tonally; he found that it had some edge over his high-gain amp and just made it sound alot smaller.
I guess, yeah. You need to take account for the patches and tailor them for the use. But then again, you do that with an amp when you play a gig in a bar, club or whatever. If the room is boomy or bassy or dead you need to tweak and a digital setup is going to be no different. The only issue is that if you use a bunch of patches and intend to use them all then you will need to tweak them all.
The upside I have found is that with the USB option and software I can easily back everything up. I really wish they'd do a software version for a handheld; the appeal of being able to have the deep level of control that's found in a laptop would be nice in something more appropriate for a gig. But aside from that my patches get backed up and I can totally see taking those tweaked patches post-gig and saving them on the laptop as a group with the idea that when I gigged there again I could just restore them and pick up where I left off.