My experiences with large injector nozzles:
First off, if you're running one of the off the shelf programmers/chips/tuners/etc do not get big nozzles. You're wasting your time and money that could be spent elsewhere for some serious gains. Why is this? The Banks PDA, PPE, Quadzilla, Predator, Diablo, etc's of the world simply don't offer enough customization to make the nozzles worth it. You could easily just buy a bigger turbo and get more HP/$ that way. Afterall, that's pretty much what everyone here wants, the most efficient way to make your truck quick. Not only are they not efficient that way, they're dangerous. I ran 1700+ EGTs when doing boosted launches with nozzles and Banks 6 gun w/pda and no matter what variables I changed I couldn't get them down. With my current tuning by Mike I haven't had anything above 1400 period.
The biggest prerequisite for large injector nozzles from my experience would be that you already have EFI Live. The level of customization available as most of you guys know is mind boggling. Not only that, but for some stupid reason a lot of the guys that sell these nozzles treat them like they're freaking Confidential: Top Secret. What that means is that you, a paying customer, cannot even find out how much bigger your new nozzles are than your stock ones (I actually had this conversation with ATS). EFI then becomes the only way you can tell how much more your new nozzles flow versus the stock nozzles.
As with any good tune, it's all about the data. Is it harder to tune an engine with big injectors vs an engine with stock ones? I couldn't tell you, but Mike probably can. I'm still a horribly rank amateur newbie on EFI, and Mike is helping me out tons. I can tell you that I have about 25,000 miles on my 35% injectors (ATS Stage IV injectors) with no mechanical problems.
We're only on version 3 of my tune and we've eliminated the smoke at idle in park, we've eliminated the smoke in gear, and we've reduced the smoke up to 55% throttle position to a slight haze. When we started we were only getting about 20k psi rail pressure when we were demanding 2600, now we're sometimes slightly exceeding demanded pressures. I know pulse width has had a lot to do with it, but I couldn't tell you specifics as I just don't know enough about what I'm looking at yet. We've also just started messing with boost. Evidently my stock turbo was running itself up to 33 psi while the vanes were open.
Seat of the pants improvements are alot of fun as well. Like I said we're only on version 3 (we're only making one or two changes per version, and then logging the crap out of it), but I did a 4wd boosted launch IN 1ST GEAR launching at 2500+ rpms and 16+ psi of boost. I ended up chirping third gear on that launch.
I don't have anything conclusive to say that X is better than Y yet as far as what size injectors, and what changes do what, just because I'm too much of a noob. If Mike wants to, he's more than welcome to shed some light on here as to what exactly he's doing to it. All I can say is that it's a lot more fun to drive, both red-assing it and as a daily driver with 73,000 on her.