I've got two Macs that I use on a daily basis. One is my primary work Mac, a MacBook Pro. The other is my primary personal Mac, a MacBook. I've got other Macs, both at work and home, but they're not used nearly as extensively as these. Each of them are set up in different ways.
When I'm in my office, my MBP is hooked up to a 24-inch widescreen LCD. The LCD is my primary monitor, sitting directly in front of me, with my MBP open and sitting on a stand to the left of the big LCD so that the tops of the two monitors are aligned.
I use Spaces, four of them. Space 1 is given over to Entourage. Space 2 is reserved for whatever I'm working on, so the app open there is most likely to be Word or PowerPoint, or maybe RDC when it's time to submit my travel expenses. Space 3 is Safari, and Space 4 is iTunes and other media apps.
For my two-monitor set-up, I use my laptop monitor as my status monitor. That's reserved for the apps which are visible in all of my Spaces, which are my Twitter client, IM, and My Day.
My dock is almost entirely empty. The only thing I keep in my dock is a folder, which opens the current build of Office that I'm using. For any other application that I use, I either let it launch on startup, or get launched on an action (say, clicking on a link that I receive in email). For the rest, I simply use Spotlight as my application launcher.
(An aside: It's a Microsoft thing to do a "daily build" -- that is, we compile our code every day. One of our goals is to have a usable version of Office created every single day. I use one of these daily builds for my work, and submit whatever bugs I happen to find in my regular usage.)
Document-wise, everything lives in the Documents folder. I've got an extensive folder structure. Since I use the Project Centre in Entourage to manage my larger projects, many of my folders are in my Office Projects folder (which I have added to the list of Places in my Finder). Most of my folders contain my own work, but I have a few folders which contain other things that I need to reference frequently.
As with my dock, my desktop is almost totally empty. I only use it for the things that I'm working on at this very instant which don't end up in a folder elsewhere -- usually documents that I've been sent via email asking for me to review them. It's my goal to have no files, other than my hard drives, visible on my desktop at the end of the day.
I always partition my laptop hard drive into two partitions: system and data. My user folder lives on my data drive, so that if (by some horrid chance) my system drive gets borked, I'm less likely to lose everything. I also keep the majority of my applications on my data drive as well.
I have an external hard drive, which I use in conjunction with Time Machine. However, I don't keep this drive hooked up to my MBP all the time. It's partitioned and shared with my Mac Mini. The Mini has primary custody of the drive, but I manually move the cable over to connect to my MBP once per week so that I've got a backup.
Hmmm, this got long, so I'll post about my set-up for my MacBook separately, and maybe add in some details about what my other Macs are doing too. And it's probably another post about how I manage my email, since that's a whole thing onto itself.