This is how I currently do it:
When initially setting up a new sound, I use Axe-edit on the computer. My computer feeds basically a HiFi stereo system - a SS power amp and then to 2 large Hi-Fi speakers with 16" woofers - old style. These have a nice crisp flat response and are powerful. I keep it loud and mix in backing tracks while experimenting. This gives me an idea of what a recorded mix would sound like (we sometimes record live direct from the mixer).
This also gives me a good sense for the bottom and hi end limits of what I can expect from a FR PA. I mainly make sure there are no ear piercing spikes, fatiguing frequencies, or thumping qualities. Then I put the same patch thru 1x12 cabs and check it out, because not all PAs are very Hi-Fi. I keep any time based FX levels much lower than I think is normal because, in my experience, once you get to the hall of wherever you are playing you will wind up with natural FX and it gets to be too much. Also, I keep gain lower so things don't get washed out live.
Finally, I do final tweaking as I go with the band. It is an iterative process. You need to do this because the hall and how full it is (people in the room) affect the sound in a big way.
After a few rounds of this, the tweaks are relatively minor. If I do tweak, usually I just lower the gain further. Because I am usually pressed for time at this point, some fast tricks for me are to just tweak the input knob (gain), simply turn off any offending FX, and let the sound man handle the other tweaks (EQ).
Most of my base sounds are already pretty dialed in, so I don't go thru this process too often (save for maybe firmware upgrades etc.).