There is no one-answer-fits-all. These kind of problems tend to require a careful investigation and I must admit I have had problems where I gave up and just changed hardware/did re-installs.
The usual things I try:
- Try disabling virus scanner
- Try disabling firewall (don't underestimate the impact this can have)
- Review the event logs (Computer Management/Event Viewer) and look for strange warnings or any errors
- Watch for anything in your startup, services you don't understand (I have used Starter in the past to review)
- Look through processes for anomalies; Process Explorer (as mentioned by Jewel S) is good for recording spikes in CPU or I/O activity while you're actually using the PC; it will tell you what process was responsible for a spike in activity if you hover over the CPU and I/O performance graphs
- There is also the possibility of something nasty buried in your devices (e.g. Starforce protection), but every time I've looked in the "Hidden Devices" I've never understood what I'm looking at.
64-bit does have more compatibility problems than 32-bit, but I don't know if there's any way to verify this to be the cause other than going to 32-bit or checking forums for 64-bit problems in relation to hardware drivers.
Personal experiences with Safe Mode have been bad - I've never fixed problems with Safe Mode (just the once I screwed up the display config and Safe Mode saved me). But then again I don't update drivers on a regular basis so I'm usually pretty clear whether it's drivers or not.
If you're running Windows Automatic Update, it's always possible that a new patch has done something and you're one of the unlucky ones to suffer deleterious effects.
You can have problems where you PC seems to hang, but it's nothing to do with CPU or hard drive blocking; I hate these problems, because they don't show up on Windows' radar. These are often low-level operations messing around with Windows' internal conversations. Firewalls and device drivers can do this sort of thing.
Falling back to a previous backup whether through System Restore or personal backup should also be tried to see if the problem disappears. If it doesn't then OMG, it's time to check the hardware...