Software
 
Vista disappointed a lot of XP users by failing to provide a VDM. The software linked will provide you with 4 virtual desktops on a Vista machine to organize your work. Amazing great stuff. This or a similar solution is highly recommeneded to improve productivity and organization.
TrueCrypt is awesome. Freeware. A variety of strong encryption algorithms to choose from. A feasible plausible deniability setup. I use this to protect any file on my hard drive that might in any way be useful to a thief. I sleep easy at night.
LiberKey is a compliation of ~250 free, open source applications. It comes as a bulk package that you can install to a USB stick to transfer from PC to PC. Many useful applications, one source for them all. It also has a self-upgrade option to keep you current on all included softwares.
GIMP is essentially a free version of Photoshop. I use it to create, tweak, and finalize all types of images for this web site as well as marketing materials to be used elsewhere. This is a great program.
CutePDF installs a virtual printer into your system. When you want to create a PDF document, you simply open the document in an editor and print to the CutePDF writer. Simple. Elegant. Very useful. Be sure you also download the free GhostScript converter on the download page.
There are a lot of graphical FTP clients out there, most of they want you to pay. CoreFTP Lite is free and works just as well as any other client I've seen.
A variedy of applications (see the one below) will allow you to save .FLV videos to disk - these are videos from YouTube or any other similar video streaming site. Say you want to save them for future reference? Use this app to conveniently play the saved file.
Download Helper allows you to save any of the in-line you-tube-like flash video demonstations posted on web sites. Works for YouTube. Save the file and use Applian FLVPlayer to view at your leisure.
For those of use who like to look up at the stars and know what we're looking at. Provides time, geoposition, and atmosphereic conditions to identify what you can see in the night sky. Maybe you just want to identify one planet with great accuracy. Maybe you want to track all the constellations. The capacity is there. All astronerds and related Trekkies need this application.
It's profoundly annoying when you download an ISO image for some disk and it turns out you don't have software to burn an ISO. MiniSoftDVD's ISO Burner is simple to use and very nearly idiot-proof. Just give it a blank disk, an ISO, and it goes to town.
Saumurize can do a TON of stuff to your desktop. Some of it is great, some if it is great only to oddball setups. I find it most useful to use as an immediate reminder of the appointments I have for the day. Put the appointments in a text file, they magially appear on the screen. Never missed a critical appointment yet with this.
Almost every Windows Registry is plagued by key values that don't exist, links that lead nowhere. It can really screw up your boot process. Eusing Free Registry Cleaner removes all unnessary and orphaned registry key values so your PC can run fast again. I recommend making a restore point before using it, just in case.
I have yet to see a better compression tool, when the goal is defined as non-lossy compression for maximum storage.
You may have to install a variety of good video and audio codecs to make the best out of VirtualDub, but it's a tried-tested-and-true tool to create professional grade movies and to reencode pieces to match the codec needs of the client.
An excellent open-source audio suite for recording, editing, and cleaning up audio.
Windows doesn't come with an SSH client. Vista and later doesn't even come with Telnet. PuTTY fills the gap.

Web Applications
 
A picture can be worth a thousand words, especially when modeling processes and concepts. Diagrammr lets you create simple diagrams online to clarify things.
A good proxy server lets you circumvent blocking software or help anonymize your web activity. There are always dozens to hundreds of these freely available servers listed here.

Blogs
 
Mankiw is a professor of economics at Harvard, advised the Bush administration, and wrote several of the most popular economics textbooks out there. He always has something interesting to say about current events.

Internet Culture
 
News aggregation and snarky commentary forums. An excellent way to waste time.
Anonymous people create a postcard illustrating some secret, then transmit it via mail. Images are posted every Sunday. Sometimes they're pithy, sometimes they're trite. They're always humanizing.
Moderately detailed investigations of an assortment of odd stories and phenomena.

Medicine / Health
 
RXList provides the FDA-approved monographs of just about every medication available in the United States. A great reference, and always up to date.
While the operators of the site have some radical ideas about the goals of pharmacotherapy, they have assembled a huge repository of research abstracts on psychotherapeutic medications.
A resource that documents the complex relationship between humans and psychedelic and psychoactive substances. The site is oriented towards recreational and psychonautic use.
A host of information about the etiology and treatment of major depressive disorder and other affective conditions.
Physicians use a protocol to select the medications to use in mental health. The protocol linked is evidence based and effective for the majority of patients with affective disorders.
The front end of this site is oriented for HIV/AIDS patients. The back end references a database that can collate the potential medication interactions of any drug. A great resource.
The Multidisciplinary Approach to Psychedelic Studies researchs the therapeutic potential of substances normally associated with recreational use. Political incorrectness makes it difficult to do good science in this field, but there is support for supervised, guided experiences in the treatment of mental illness, especially Post Traumatic Stress Disorder.