I actually don't own a POD HD500, but I convinced my brother to buy one and have had the pleasure of experimenting with it a few times. I use PC amp modelers now and have used amp modelers since I bought a Boss GT-5 back in '96. If I wanted a hardware unit, the HD500/x would be my first choice. There is a steep learning curve, but as you gain clarity on the basic functioning, everything else will be much easier. If you don't get the basics down, you will remain confused and frustrated as you attempt to program new sounds. Others have already covered the GUI, so I won't go into it, but will concentrate on some basics, and how to get approach getting the sounds you want.
An oft overlooked aspect of learning new digital gear is the internal level structure. It's really important to get a handle on how the volume levels function from input to output, and to leave ample headroom when driving external gear. You can probably leave the "Guitar In" pad switch off. Keep in mind it will affect the preset inputs if changed. The input level to the amp model is very important regarding attack character. You might want to run an eq b4 the amp as a "trim" adjustment b4 the amp. Seems to me that should be included at the beginning of the signal chain anyway. I find that the peaks of saturated sounds should be at least ~6dB below the full output level, so clean sounds will have enough loudness in comparison. I imagine it is quite possible to distort the HD500 output stage as well as any external gear it goes into. Check the internal HD500 software mixer levels, and I'd keep the Master hardware knob on ~12 o'clock so you don't overload external gear. It's important to note that setting both input paths to the same option and running mono FX will increase the input signal 6dB -- as will setting both software mixer knobs to center, potentially overloading the output. It's something to experiment with and set accordingly for each preset. It would be great if they implement M/S knobs in the software mixer so when you run two amps: one can be focused in the center of the mix, and the other at the sides. If there is a stereo house mix, it's better for the off center audience members not to run paned stereo signals.
One thing you need to really learn to listen for with amps is the response, or "feel", as well as the overall tone. The response has to do with how the tone is shaped over time. It's been the biggest complaint with modelers since the beginning. Good sounding tube guitar amps usually create some treble ducking when turned up loud and your picking attack is strong. Different tube types also have different gain envelope shapes from a smoother to harder breakup and varying degrees of generated even and odd harmonics largely depending on the operating class mode: A (even and odd) or AB (harder sounding odd only).
Beam tetrode power tubes like the KT66 used in the Marshall S100, JTM45 & Route 66 amps, the 6V6 in the Fender Deluxe, and the 6CA7 in Hiwatts generate much less 3rd order harmonics than pentode tubes like EL34 or EL84, but the 3rd harmonic in the guitar string will still be accentuated as any amp is pushed harder. Still, they tend to break up sweeter, but require a negative-feedback "Presence" control from the transformer to damp intermodulation distortion. Another thing that tube amps exhibit is a type of S-curve gain recovery created by the rectifier, output transformer and/or power supply. It's what gives it that certain sponginess that we call "feel".
Someone mentioned trying the preamp versions of the amp models. Certainly, you can get some good tones with the preamps, but they won't have the sponginess and harmonic richness of the amp models with the amp DEP Master level set up high. They will however generate both even and odd harmonics, being that preamps are class A and don't cancel the generated even harmonics like class AB amps do. Nor will class A mode generate the hasher random harmonics that crossover distortion in class AB mode does. The guitar speaker should generally filter out some crossover harshness, so it's often not a problem -- too many factors to give a definitive answer. These factors can all be adjusted with the DEP settings. I think there should be some better descriptions of the DEP controls. Below is my interpretation of the factors they affect:
Master: sponginess and harmonic richness
Bias: boldness and generated even harmonics.
Bias X: gain compression linearity = smoothness of breakup.
You may want to adjust the Master DEP and/or the Channel Output after adjusting the Bias or Bias X, but the SAG is also part of the equation. Once you grasp what they all do, you can start to really make use of them.
The Speaker Cab DEP descriptions seem adequate and are a really great addition. The Decay control is actually speaker damping. It can roll off the highs as well as affecting the tightness. You probably want to set up the Amp DEP first, then fine tune with the Speaker DEP. Strong cab resonances and loose speaker damping can mask the amp response/tone. What can I say, you'll get to know the cabs as you try them. Open backs generally have less bass and looser response than closed.
It's difficult to describe the mics, but they all have frequency and subtle resonance characters. The SM57 is the "go to" guitar mic. It accentuates 4-6 kHz, so be aware of that. The ribbon mics are more neutral and nice to start with. Ribbons have fast transient response, so they can be a bit crisp on bright high gain tones. The U67 Tube condenser can smooth out those tones. The Dyn 409 is bass heavy, and might be best for really heavy metal tones. The Dyn 421 is another go to, but it's a bit sharp in a certain way in the high end for my tastes. I usually avoid on axis mic positioning, but it can sound right for certain crisp tones. Maybe they should have included more mic positioning ability, but things are definitely more manageable without it. I've gotten lost in positioning mics with PC modelers. Hours pass wholly unaccounted for.
Another thing to know is that guitar amp tone stacks are calibrated for a few reasons so that the bass and treble are boosted and the midrange is dipped with the knobs set flat. The presence knob normally smooths out amp resonances, but it may just be another eq point depending on the amp model. It's worth experimenting with turning the mids up, and turning the treble, presence and maybe bass down depending on the gain level and your pickups/pot/guitar cable combination. You can get some really sweet creamy tones with such settings -- particularly with a low C cable and good low H pickups.
As far as where FX go in the signal chain, mainly be aware of whether the FX are stereo or mono. I usually run modulation pedals b4 the amp and sometimes b4 distortion pedals, but there are no set rules. A delay b4 an amp will have a less linear decay as the amp gain recovers. Running two or three modulation pedals in series can be really cool. Arrange the order to what sounds right to you. Reverbs are usually best after the amp, but keep in mind that spring reverbs are wired in between the preamp and amp -- if run b4 the amp, it might sound better if there isn't much preamp gain. Experiment.
Well-calibrated guitar tone is a matter of understanding the contribution of everything in the signal chain, including the pick shape/material and strings. After 20+ years experimenting with various materials, I've finally gone back to Acetal for my standard flat pick. Steel guitar strings can sound harsh or thin. I prefer nickel-based alloys. Thicker strings can sometimes actually sound harsher, because the transverse waves in the attack can fall in the harsh ~3kHz region. It depends on the scale length and string material. If the strummed attack is too hard sounding, you might want to change string gage or material.