It really really depends. Making an amp sound good live is not easy either - specially in small venues.
I've rarely struggled to be honest. Like... genuinely, I can't think of many gigs where my tone was bad.
The main time - I played an out-door festival on a big stage, audience of 1400 or so. Full stack behind me; two 4x12s... and I stupidly didn't have a long enough cable to plug into the bottom cab, so I plugged into the top. I was right in the beam of the speaker, and it was horrible to listen to, and it did affect my performance.
But the crowd didn't notice any of that of course. Because they were getting the FOH sound; because you don't typically hear the stage sound in that kind of environment.
Whereas you hear a lot from the stage in small clubs. In those kinds of environments, I turn up to the drums and make sure I'm not quiet, and not too loud. There's a sweet spot. I get my EQ dialled correctly, and I try to make sure the audience aren't getting blasted with the beam.
Audience habits helps quite a bit with that because in small venues, people rarely stand right up against the stage.
The other times were when I was using underpowered amps, or having to borrow some house amp piece of shit. I've always been resolved since those early days to not put myself in that situation. I'll jump on a bus with a 50-watt 5153 before I borrow another Fender FM 1x10 combo like I once had to in 2008/2009 !