Question for photomatt if you're still reading this comment thread, and since it might be my only chance to get dialog with you. Are you considering any changes regards the stack, since many installations can have a issues with speed now (not intended as a criticism). So eg something like Postgres, or MongoDB even for the DB Backend?
Running WP.com, I'm very sensitive too the performance implications of our stack. A small percentage change in performance could mean the difference of racks of servers for us. At Automattic we've also had a peek behind the curtain of pretty much every high-scale WP installation out there. The vast majority of performance issues I've seen are not from something intrinsic to PHP or MySQL, but how people configure them…
Again - I'm not advocating that you switch the default, but if switching database engines is not your bottleneck, then would you be willing to consider that option (maybe Kickstarter it)