We've covered Postbox in the past, and I've been using it regularly since the beta. Version 2.0 was just officially released, and there's a lot to love in the latest incarnation of this Mail.app replacement.
Postbox already had some great organization capabilities, including "Conversation" views for email threads, and "Topics" for tagging messages and quickly sorting them. With version 2.0, organization is faster and even easier, thanks to features like Quick Move and some new keyboard shortcuts. There's even a Quick Reply feature that lets you respond to a message from within the message or thread by hitting Shift+R (a lot like GMail). There are also keyboard shortcuts for navigating mailboxes and accounts without touching your mouse.
The new Universal Inbox and Account Groups views make it easy to manage multiple accounts and multiple inboxes from one screen. Combined with the tab features of Postbox, you can effectively handle quite a few accounts with very little effort. There are also new "Focus" panes, where you can view To-Dos and filter by Has Attachment, Unread, Topics, Favorite Contacts, and Dates. For a full list of new features, check out the Feature List at the Postbox website.
Postbox is free to try, and US$39.95 for a license. There's also a free version, Postbox Express, if you don't need all of the extra bells and whistles. There's even a Windows version available! Check it out (especially if you're a keyboard lover or running Mail.app with Mail Act-On or similar).