Microsoft Outlook is my best friend. I have rules set up to push messages that are newsletters, MFI replies, new Twitter follows, facebook messages, etc. into specific folders. This allows me to focus on messages that more critically directed to me and not have to filter through as much in my inbox. When I get the free time to flip through the other folders I of course do so and reply when I can. It's tough to juggle, and with multiple email accounts it sometimes complicates things as well.
It will be interesting to see how Google Wave impacts email.