You don't have much choice if you're getting your distortion from the amp. It's either between the guitar and the amp, or in the effects chain via the amp. Put it in the chain and the signal will degrade less.
When the distortion comes from the pedal, put EQ after the pedal to change how each frequency sits in the mix, and put an EQ before the pedal to change the character of the sound. If you crank the bass going into the pedal, you'll get a really fuzzy sound like a big muff. If you scoop the bass, you'll get less fuzz and as a result more clarity. If you crank the mids going into the pedal, you'll sound like Pantara. Visit the link in my sig and scroll to the bottom to hear a demo of that technique.
One interesting technique I used to play with was boosting at 500hz going into my distortion pedal then scooping it a bit after the signal was distorted. I don't anymore, because there's too many pedals involved for my taste and I'd rather just get better distortion directly from my amp.