Well I just got myself a unit recently. Before that I tried out the desktop Tonelab and PODxt. Yes, it does have a warmer/more natural sort of sound compared to the POD. But it doesn't stack up in terms the sheer number of effects and depth of tweaking on the POD. Plus the POD has the PC interface and upgradable firmware going for it which the Tonelab SE doesn't have. On the PODxt live and GT8, you can (for the GT8 at least, not sure about POD live) bypass their amp models and run your own amp's preamp through the unit and just use their onboard effects only to integrate with your existing amp.
The main thing that sold me was the natural amp sound. I'm more of a feel/dynamic sort of player and my ears have been sullied by the tone of full valve amps. It feels dynamic, meaning that it reacts to my playing. For eg, the saturation sweetens up and sings the more aggressively I play, and the tone cleans up when I roll off my volume. On the PODxt, I found it a bit linear. The amp models sounded great but didn't have the "feel" I was after.
Effects on the Tonelad SE are okay and useable. Couldn't replicate the lush chorus of my Voodoo Labs analog chorus, but that's nitpicking. I managed to tweak the wah to approximate the sound of my v847 reissue I know and love. So it might be I just need to be a bit patient and tweak around until I find a setting that blows me away. Time spent in tweaking is the same for any other multi unit IMHO.
In the end it boils down to what you want to use the unit for. A lot of pro musicians I know go with the PODs 'cos they can just take the same patches they used for recording in the studio and recall them when doing gigs. I've played with some of them using the PODs in a live setting and they don't sound bad. For me what I wanted most was the natural valve feel which the Tonelab SE had more of and a simpler setup so I didn't have to spend a lot of time working my head around the mind boggling number of parameters the POD has to come up with a sound I like. I'm not patient that way.
Haven't done any gigging with the unit yet so I can't tell you how it holds up under normal abuse. I'll carry a spare 12ax7 just in case...