Nambu is a feature-rich Twitter app for Mac OS X that supports many social networks. It offers plenty of configuration options but has simple defaults for beginners. It also has excellent integration with its sister services, tr.im and pic.im
DestroyTwitter is a full-featured yet lightweight Adobe AIR twitter app. While many other AIR apps are guilty of being on the pudgy and/or sluggish side, DestroyTwitter is refreshingly responsive. Upon load it starts at about 40MB and after using it for a bit, searching, and loading a couple other columns it only climbed to 61MB. Very good for an AIR app!
Even though the memory footprint is light, it doesn't skimp on features. The app is maintained by Jonnie Hallman, an Experience Designer at Adobe, so that may have something to do with it.
TweetDeck is a feature-stuffed multi-column Twitter app for the iPhone. It is already a major desktop twitter client, running on Adobe AIR, with all the features anyone could ask for (including multiple accounts as of 0.26), so it seemed like they would spend all their time making a great user interface. They packed it all in there, but at the expense of usability. From their website:
TweetDeck is an Adobe AIR Twitter app for power users. Using a column layout, TweetDeck allows a user to set up many feeds at once. Some are specialized to Twitter, such as your friends, @ mentions, direct messages and so forth. But the real power lies in their numerous advanced search features, which filter the public timeline any way you desire: