I have a 40 so I have plenty of room. About half of it is filled with music. I also have my entire hard drive backed up as well as multimedia content and articles on it that I do for freelance work.
On the Mac Ii use iTunes and iSync with it. I also downloaded driving directions from streetfinder and copied them into a notes files and used the Notes function on the iPod.
For the iPod, I have an iTrip for car trips, a Creative TravelSound for the bedroom, a naviPod for wireless remote control, an iTalk for recording interviews (much better than the first microphone for the iPod) and a Media Reader for transferring photos when on trips. Oh, and I have a Belkin battery pack for long plane trips (I travel internationally on a regular basis).
I've gone through various skins and am happy with the new Exo2 glow skins (white).
I manually manage the iPod so I needn't have my hard drive filled with almost 20 gb of music, but I do regularly backup my music onto an external hard drive (using PodUtil).