1. Nginx Fastcgi Cache - From the personal results I've experienced so far this easily beats and replaces a significant portion of other caching systems like supercache and w3 total cache.
It's also been very handy for cutting back on image processing and serving outside the typical caching benefits.
blogs.php causes a lot of unnecessary additional load on the server because it uses php to find and serve static files. With nginx fastcgi_cache the response from blogs.php can be cached so its served as fast as any other static files. This works across multiple blogs and domains. You can control cache times based on whether they or not they are users. For example if they are a user you might send them cached pages of up to 30 minutes old and if they are not a user you might send a cached response of a day. If its a jpeg you might set the cache to 7 days plus add in browser caching in the headers.
If you've got this kind of set up on something like Amazon you can set up a terabyte Elastic Block for nginx to cache php responses on there. I haven't tried it yet but in theory you could in fact cache to multiple terabyte Elastic Blocks in Amazon or any mounted network drive. This means a lot of your caching is done for the cost of extra disk space and you're not just restricted to one computers disk space. Thats something that has held supercache back over batcache. Batcache you have to purchase more memory to expand. Nginx fastcgi cache will not solve all your cache problems but it works very well with a batcache solution.
After the success in eliminating the load I replaced blogs.php to include dynamic image resizing eg:
/files/2009/12/megan-fox.jpg?w=345
This is helpful for themes that have all kinds of custom sized images in the template. blogs.php will do the resizing once and then nginx will served the cached version of the resize for as long as you specify.
2. Google App Engine for Image Processing and Serving statics - The above solution is pretty cool but I was thinking as you get more and more users statics obviously take up load time (although this isn't such a big deal with nginx.) Image processing however takes up more and more cpu time on your server. I was thinking it would be call to have a Google App Engine app which provides a service to your mu installation and does all your image resizing and serves all images as well as the core wordpress statics. That way you remove the image processing to a firstly free, then very affordable solution with virtually unlimited scalability for these features.
You could also tack on the functionality which converts javascript files into the one php file.
Anyway those are a couple of ideas.