I agree with the other post here. Basically trial and error. Most guitarists change their tone over time. Clapton sounds a lot different now than he used..not in terms of the licks he uses but in the actual timbre of the sound. Again, as someone else said here, this is made up of a lot of variables.

I change my sound often. This being the case, I tend to run a clean amp with external stomp boxes to get the sound I want. For some reason Overdrive/Distortion seems to be the one I change most. Currently I'm using a Marshall Blues Breaker pedal. Kills with a Janglebox compressor. I was using a VS Route 66 (comp and overdrive) a few months ago. Probably will change again by the end of the year. Even with all this though, the guitar still sounds best through a tube overdriven amplifier.

Jax Music Supply