I've been using an HD500x into the front of a Morgan AC20 Deluxe, and couldn't believe the tone suck at first with the HD in front of the amp. I had to use the AC30 amp model just to get close to the sound of the Morgan when plugged directly into it. At rehearsal on Thursday, our other guitar player (Matchless Lightning 15 tube amp, very nice stomp box setup... oh, and he can play, probably one of the best players I've ever known) tweaked my Morgan and POD and got very close to the sound of his rig. The biggest difference is the clarity and thickness of his delayed signal and the lack of digital color on overdrive sounds (he uses a Timmy).
I play P&W, and played lead today on two songs. The 2nd song has a sustained high F and Bb played together on the 18th fret of the 1st and 2nd strings at the end of a chorus... it hangs into the next verse, and I got two full bars of sustain while fading out with the volume pedal over 8 counts at 62 beats per minute. I never got that kind of sustain with the DT. The DT is a great amp, that is easy to dial in, but I'm convinced now that it can't match the feel of a real tube preamp. Playing the POD into a tube preamp is totally different than playing into a DT25. The touch dynamics alone were worth the switch.
Setup is Blue Comp>Screamer (30% drive)>Screamer(50% drive and slight boost for leads)>AC30 Amp Model>Analog Delay w/Mod(1 in each path both with heavy trailing modulation, left set to 8th, right set to .8th almost always use one or the other, rarely both at the same time)>Bias Modulation (for a chorus/tremolo effect without the pitch change)>Hall verb (not used much)>Octo Verb (used on both light overdrive and clean sounds to add a little sparkle)>AC20 Deluxe head>Morgan 1x12 cab loaded with an Alnico Blue.
I add this to say that the POD into a great tube amp can get very close to stomps into a great tube amp, but the POD WILL mask your sound in a way that stomp pedals won't. If the POD was true bypass, with a more powerful DSP (needed to uncompress the overdrives and distortions) it could compete head to head with a stomp rig.