I had a go with a specific music distro once, may have been KXstudio. I seem to remember there was a tool for linking input, outputs and processes that was a bit confusing. I gave up in the end. That was a while ago and things move quickly in Linux land. I doubt it's still like that.
I've given Ardour + Jack a try on Lubuntu / Xubuntu in the past. Bit of a learning curve (like with most things in Linux, for me) but I had the setup working with an M-Audio interface without too many hassles. The deal breaker was that most of the VST plugins I'm fond of didn't work well with this setup. Jack was also a little buggy IIRC.
This was quite a few years back so I don't know if the landscape has changed. I've never bothered giving it another go.
@Robstafarian (tagging in case he turns up) used / uses Ubuntu Studio if I'm not mistaken.