My advice is to go Guitar>Amp>FX Send>POD Input then POD output>FX return. This (in my opinion) the best setup for amps as far as keeping the inegrity of the signal. When I run the guitar straight into the POD and then into the amp, I lose integrity. In other words, when I switch on my distortion, it loses a lot of gain, even if/when I can get my clean channel to sound almost identical. The only problem is if your amp doesn't have a footswitchable FX loop button. Surprisingly, many amps don't, but if your amp does, go with the FX loop. If you DO go with the FX loop, make sure to check the rear panel of your POD (the panel with all the input/output jacks) and set the "Amp/Line" switch to "Line." This will give you the purest tone (in my opinion) as it switches the POD to "studio direct mode," which bypasses the POD's preamps and only adds on the effects you assign. I hope this helps! Also, I would like to add that I'm playing through an Egnater Vengeance, which is a pretty high quality amp, so the scenario could be 100% using a Marshall Valvestate. If you try my recommendation and aren't satisfied with it, please don't think any lesser of me, it's just what I've found that works for me! :)