For me it depends on what amp I'm using. The Marshall has a gain stage so I generally run that with some amount of grit/overdrive. Like Robert I'll add a pedal to that signal for over the top lead distortion. My new Maxon SD-9 clone is perfect for that. On the Fender amp I'll just run one distortion/od pedal but I mostly play clean on that one or turn it up loud for natural overdrive.
Guitars/Bass - MIM Fender Classic 50s Strat, MIM Fender Standard Strat, Squier Classic Vibe 50s Tele, Gibson Les Paul Studio, Epi '56 Gold Top Les Paul, Martin DSR acoustic, Sigma Martin Auditorium electric/acoustic, Squier Jazz Bass.
Amps/Cabinets/Modelers - Model 2558 50 watt Marshall Silver Anniversary Jubilee combo w/ Celestion Vintage 30s, 4x12 Marshall cabinet w/25 watt Greenback Celestions, Fender Blues Junior w/ a couple of Billm mods, Line 6 POD 2.0, Roland Micro Cube
Pedals/Effects - Cry Baby Classic Wah, Boss TU-2, Boss NS-2, Boss RC-2 Loop Station, Ross Compressor, MXR Micro Amp, Danelectro FAB Echo, Danelectro FAB Chorus, Danelectro Chicken Salad, Marshall Guv'nor Plus, Marshall Echohead, Duhvoodooman's Zonkin' Yellow Screamer, Digitech Digiverb, Digitech Bad Monkey, Dunlop Fuzz Face, Homemade Loop Bypass pedal, Duhvoodooman's Sonic Tonic (Maxon SD-9 clone +), Voodoo Labs Superfuzz