I am using various Sysinternals' tools from time when they were still called Winternals. Among all those tools there is one I use every day - Process Explorer. It is replacement for Task Manager and you can even configure it to use it's shortcut (Ctrl-Alt-Escape). However there are few problems.
Selecting a program
Task Manager allowed you to select program by typing first few letters. Typing EXP (fast) would select explorer.exe. In Process Explorer there was same feature but somehow it got lost during updates. If you type EXP there you will end up with P*.exe selected. This caused me to kill wrong program few times. This is fixed in Process Explorer 14.
Although Process Explorer does support 64-bit windows it does it by packing 64-bit executable within his 32-bit executable. Solution is definitely strange and has one awful consequence - it needs write rights to his directory in 64-bit Vista.
Everything else :). My favorite would be search for open handle - it solves that problem when one process is holding file open and you cannot delete it (or eject usb drive) because of it. Also useful is option to track memory usage history per application. Total control over what exactly is displayed is just a cherry on top.