I recall a thread similar to this being made a while back in the context of freeware on OS X, and while there was some variety in the replies, I think people tend to come back to having the same obvious ones in mind- Quicksilver, Adium, etc. Shareware projects, usually available for purchase at minimal cost but not entirely free, tend to serve more niches to a fuller extent, though, I feel, so I thought it'd be interesting to do this for shareware since it would possibly even bring out specific areas of computer use from each poster that others hadn't thought to enhance. At the same time, I'm limiting the software that can be considered here because obviously a huge commercial suite like MS Office or Adobe CS3 has a few advantages over others, and most don't really fit the whole "serving a niche" description. Anyway...

I'll start this off by casting my vote for USB Overdrive.

This is an app with preference pane that lets you control what every button, scroll wheel, trigger, or whatever on your USB input device does, whether it be a special kind of click, a hardware function a specific keyboard input or even opening a file or app. Much more flexible than the mouse drivers I otherwise would be using and less annoying overall (the mouse I'm using currently apparently doesn't work so well when used with Logitech control center...), I pretty much never have to worry about whether a USB device says it's "Mac-compatible" anymore thanks to this app (I've used it with the Logitech MX518) and I don't have to let precious extra mouse buttons go to waste on pointless functions the manufacturer decided would be a cool feature. Definitely worth the cost to me, and anyone else that wants to be something of a control freak with their USB (or Bluetooth) devices.