If you run it in the loop (amps fx send to GNX4's input and GNX4's output to amps fx return) just for effects and plug your guitar into your amps input, then you need to bypass all amp and cabinet modeling. If you want to use it like you would hooked to a computer using the amp modeling, then you will need to plug your guitar into the GNX4's input and run it's output to the real amps effects return, and bypass any cabinet modeling (since you're already going through a real cabinet).