I've been using FastMail.fm for around 4 years now. It's absolutely worth the $40/yr. I manage a lot of email accounts, and FastMail lets me define rules to file emails from different accounts into different folders, and automatically set my from/reply-to address based on the folder I'm in. Their spam handling has been excellent and there are tons of other small features like one-time-passwords which are great.

That said, I do find GMail's interface "snappier" than FastMail's, and threaded conversations are definitely nice to have. I'm starting to see GMail's benefit in tagging messages instead of using a folder hierarchy, but for managing email from multiple accounts, FastMail is definitely easier.