The weak link in iTunes is the actual D/A conversion on your computer. The output of most computers' sound cards is simply atrocious, and the iPod isn't much better. But, if you have a quality outboard DAC, you can make iTunes sound like an audiophile-quality CD source.
A few weeks ago, I picked up a Benchmark DAC1. After listening to the improvement on my CD player, I connected the DAC to my computer via an optical TOSlink cable.
Now, I can't hear any difference between music in iTunes (the lossless encoded files) and my CD transport. The quality simply blew me away.
The CD player is a Simaudio Equinox CD Player (a phenomenal-sounding player on its own), but the Benchmark DAC sounds even more detailed and open than the player on its own. So, getting the equal quality of out iTunes (via the DAC) is quite a feat.
Try it. You'll be shocked at how good it sounds.
Disclaimer: this won't help your .mp3 or iTMS-purchased songs -- but Lossless audio plays incredibly well.