Unless you configure the drive from a few levels under Administrative Tools, the drive will appear to randomly select a letter. For example, one day when you plug your USB drive in, you'll see E: and on another occassion you'll see F:. It's not really random--its actually tied to which USB ports are available and the internal definitions of the ports by sequence. This can be troublesome should you have shortcuts on your desktop that point to programs on your USB drive. The install packages would have dubbed the starting and target destinations with whatever letter the USB drive had at the time--so when the drive letter changes, the shortcuts don't work! 
To solve this heartburn, do the following:
- Go to Start>Control Panel>Administrative Tools>Computer Management>Storage>Disk Management
- Highlight the drive and select Change Drive Letter and Paths..."
- Click on Change.
- Type a higher letter (e.g. S,T,U,V..) so that if you were to get a new internal disk drive, the assignment won't conflict.
Once the save is changed, go through your desktop and your program shortcuts by right clicking on the shortcut's icon. Select Property. Reassign any icons, targets and starting destinations with the drive letter you assigned.