A combination of Address Book groups, Spotlight, and Smart Mailboxes allows me to stay on top of client emails.
- Create a group in Address Book (e.g. "Clients") and add all the corresponding contacts to it.
- Create a new Smart Mailbox in Mail for messages that matches All of the following conditions: Sender is Member of Group [e.g. Clients]; and Date Received is in the last 7 days.
- Now, here's the cool part. From the View menu, select Sort By: Message Status. All messages that you have replied to will be at the top of the list, sorted reverse-chronologically. Messages you have not replied to will be at the bottom. Now click the Message Status column heading (the dot that should be highlighted already) to reverse the sort order. Messages that you have not replied to will be listed at the top of the list, oldest first.

