Sweet rig !

I get the impression that you are thinking of using the modelling on the HD to replace your Mesa (rather than for straight MultiFX)? If so, there are others on the forum who use the HD more intensively with modelled amps for live performance 

If not ...

I have thus far used the HD for performance only.  I use the HD500 primarily for FX and have a patch bank devoted to that.  I also have a second bank containing identical patches but with modelled sounds.  I use this as a backup for my amp.   

I run the HD with a JVM410 Combo using the four cable method (which is a headache to setup initially but works very well once balanced off against your rig).  The JVM supports MIDI so I use the HD for switching also.   That, along with guitars (70s Strat with EMG 89/SA/SA set, Gretsch 6119 Tenessee Rose, Gibson "The Paul") is my whole rig at present.   My band plays originals - hard rock/garage/indie/classic rock/country tones with a dash of metal thrown in.

I have four generic patches (clean, light crunch, heavy crunch/OD and lead).  Each of these has four footswitchable effects and something assigned to the Expression Pedal (Wah or delay level).

I also have about a dozen song-specific patches which feature very specific effects setups/boosts etc.

I typically have a handful of 'messabout/in progress' patches around too which I shake down when jamming.

I have 2 seperate preset lists.

The first preset contains the patches with cab-modelling on (for use with headphones, direct-recording etc.) and the second list contains the patches without cab-modelling where i've tweaked the patches to sound the same as the ones with cab-modelling on.

I connect the pod through the fx-return of my amp-head. When in the rehearsal-room I just krank up the volume, on stage the cab get's mic'ed.

I have one generic ABCD for the main-sound. (A. Clean, B. Gain, C. Lead, D. Weird shizzle)

Other banks are ordered depending on what the songs are demanding.

This set-up works just fine for me

Sorry to bump an ancient thread, but I couldn't find a more recent discussion of this topic. 

I've had my hd500 for a little over a year, and I've been using it practicing and gigging with my band.  I recorded with it some.  Here is a brain dump of my rig and experience with it.

I am in a 90s rock cover band based in Atlanta.  We're called Flannel.  We're a 4 piece and I am the only guitar player. plug: facebook.com/flannelATL.  I have 2 strats (1 w a floyd and bucker), 1 tele with humbuckers in it and a weird gibson les paul thats just mahogany.  I run the hd500 into an old ATA T100S 100w power amp (takes 4 el34s).  It's 50w/50w in stereo.  My backup is a peavey classic 50/50 (which takes EIGHT el84s). I run one cable from the guitar to the pedal, two cables from the pedal to the back of the power amp, and 2 cables into my 5150 4x12 cab, 8 ohms, stereo.  I run both sides of the power amp wide open, and then manage the overall volume with the master volume on my pedal.  I think my tone is killer and other folks seem to agree.  My rig is quite simple and I can set up in a matter of a few minutes.  All my cables are color coded.

I see some of you guys are using some general patches.  I dial in a patch, sometimes 2, for each song.  Sometimes I'll have two tones that are so distinctly different, I couldn't get from one to the other by turning on a fuzz or whatever, within the patch.  You oughta know, for example, (we have a female singer) has a patch that has reverb and tremolo going into a fender amp, for the verse parts.  I have a footswitch that toggles those off and kicks on a tube screamer for the pre chorus.  I have a complete other patch for the actual chorus where the wah pedal is on and engaged and it's already dirty.  This way, I can switch straight from the second setting of the first patch into the chorus and drop right back into the first setting of the first patch when the verse kicks back.  This pedal is really great for that sort of stuff.  Our transitions can be tight because i'm not doing a whole bunch of ******** tap dancing.  We've only recently started gigging (fewer than 10 gigs under our belt, all in the last 4 months, although we've been practicing for about 18 months).  Sound guys feel really comfortable with it.   I really love running this pedal into a beefy el34 power amp.  It's probably just psychosomatic ********, but I feel better running into a tube power amp for the "warmth" or whatever.  Whatever it is, it's got *** for days.  that power amp is a god damned monster.  I'd like another 4x12 cab for maximum face melting powar but that's down the line a bit after other bits of gear and you know, bills.  I'm going to need a rack mount stereo EQ as soon as possible so I can overall adjustments to my tones on the fly, based on the room. 

Like I said, I build patches for every single song. Within those, I try to use the internal toggles as much as possible, as long as I can make the levels work and it sounds right.  I line up my effects based on what I need them to do in the song.  fs1 is always going to be the first thing I need to do in a song.  Kick on the distortion, almost always.  I REALLY wish I could make names for the tags that show up onscreen on the pedal.  most of my toggles end up saying 'multi' so they are basically ******* useless.  how about you let me decide what goes in those 5 measly characters, line 6? anyway, fs2 will be my secondary thingy.  maybe it's the bridge, or usually some effecty thing, like a flanger on counting blue cars.  If I am using the wah for my solo, I will be lazy and put all my lead stuff toggled to the wah footswitch.  I'll usually add some delay, compressor and extra gain for solos, and so i'll just have those tag along when I kick on the wah.  Then my tone gets nice and dry and crunchy when I drop back into the rhythm guitar part.  No tap dancing.  Sometimes I *won't* tie the expression pedal effect to the toe switch button.  For example, on killing in the name, I use a whammy pedal.  I usually want to end the solo with the pedal in the heel position, so I can't use the toe switch to disengage it.  So, it sits on fs 4, because it's right next to the expression pedal.  Usually fs4 is reserved for an extra distortion if I need it, or it's basically always on when I am playing my all single coil strat (so it has enough oomph to keep up with all my other guitars which have humbuckers).  I've never needed more footswitches than I have available to me without being able to just use a second patch.  I'd say the main drawback to my system is that it can make it difficult to call an audible on a song if I don't have that particular patch loaded or something.  I can usually scramble and grab another patch that is in the ball park of what I need to do.  That occurred to me at our last show, so now I plan to build the set list as normal, and then instead of having the rest of the set list blank, I will put everything else beyond our set, in alphabetical order.  That way, if we need to play something that is not on our set list, I can still get to it without trying to kludge it with another patch.

I have issues getting my levels even across 40 some odd patches.  To the absolute surprise of nobody.  My band has had to burn a couple practices where I have my laptop and the singer is making mixer and channel adjustments to my patches to get me level with the band.  Each song has its own needs.  Getting levels even seems like it should be easier.  The various amp models are all over the ******* place in terms of volume, which makes my life very difficult.  Speaking of the editor, it is both wonderful and terrible.  line6, you guys REALLY need to have edit history built into that thing.  There's this new thing. It's called ctrl+******* z.  maybe you've heard of it.   That I can't go back and forth between a change and the tone previous with one click or keystroke is just stupid.  Yes, I can recall the original patch BUT THAT IS OBVIOUSLY NOT THE SAME THING when I am 6 changes deep into a patch and I forget what the setting I just changed was.  A history function would make the hd500 edit software a true sandbox.

I do not understand how I should be using cabinet emulation.  Should I? I am running into a cab, so I feel like I should not.  When I originaly designed all these patches, it somehow hadn't occurred to me to turn them off, but I have been experimenting a little with no cab emulation and am finding that it really helps with some sounds (especially clean tones for whatever reason).   I do a lot of dual amp stuff in stereo.  I don't know that I particularly need to, but I can, so I do.  It's fun!  I do this quite a bit with some of the balls out heavy rock stuff we do.  I know on song 2 I think I am using like a plexi with a fuzz in front of it and also a rectifier or some such thing.  I get the ratty, assy sound of the marshall/fuzz but I also get that tight percussive metal tone.  Yes, I run stereo live, and yes, I mike it on both sides of my cab and run into two channels on the mixer.  

There is a ton of deep edit stuff that I just really don't touch.  I am a pretty technical dude but **** I have a life, too.  I'd like to try out some stuff on customtone, but it's too big and disorganized to be useful.  I don't want to search 40.000 records alphabetically, and the search is shitty.  Why would I even want to hear someone's patches they made for their headphones when they are going to sound like garbage running through an amp?  Frankly, I am not convinced of your average forum users' taste, no offense.

Overall I think the hd500 is great live.  I've got a ton of versatility and it's very expressive.  I feel like it helps me put on a great performance because I can either dial in much the same tones as I hear the bands use in recordings, or I can do something that evokes the same spirit when we change a familiar tune up somehow.  Once I am beyond the onerous task of getting my levels settled with the rest of my band, the performance is easy.  I don't even need a hard copy of the set list because I can see what is next on my pedal.

Anyway, I hope that helps.