A lot of great tips in this thread, including EQ being the main focus: Training your ears to hear how that upper-midrange cuts in a mix while making your tone isolated sound brash and almost "annoying" is the key. Make sure you dial in your tones at the volume you will perform at and also use backing tracks to see where the tone fits in the mix and/or pink noise.
to add: How and where you place the effects in the stereo field will also make sure your tones cut through the mix and not get lost. The prime example is if you look at the eruption preset, the reverb is panned to one side. This ensures the dry signal will always get through while the wet effects are coming on a different side of the stereo field.
This is the basis of most WDW rigs. Scott Henderson and Mike Landau also use a Wet/Dry rig where one side is fully wet, the other is fully dry and then they're blended either by FOH or the volume is controlled by the player. Many players utilize an expression pedal blend the wet effects on the fly, including myself.
When playing with a real guitar cabinet, since the back of your legs don't have ears, you'd be surprised how loud most guitarists actually play without realizing it. Your proximity to the cabinet is usually the culprit as well as your actual physical height. If I play with a guitar cabinet live, I always try to make sure I record a loop (at performance volume) on gigs and actually walk out in front of the cabinet and even into the audience section and hear what my tone actually sounds like. The influence of the room can really change your EQ without you realizing it when you're standing 3-4 feet in front of your cabinet while playing.
Lastly, I would also utilize the ducker feature in a lot of time based effects. This is how many shredding players can still play a ton of notes without the delays getting in the way until they hold a note for the sustain.