As mentioned in someone else's post, it is PortableApps.com. I left it off as I didn't want to be self promotional in the reference. Mine is far from the largest Drupal site, so other sites like Weather.com and The Onion have done more with large-scale scaling in terms of multiple servers and the like. Personally, for PortableApps.com, I've used Advanced CSS/JS Aggregation [1] and LABjs [2] to help quite a bit in terms of caching along with offloading images and static scripts to a CDN (MaxCDN in our case). Moving the MySQL data from a standard server-based instance to Rackspace's Cloud Database instance and the Drupal install from a dedicated server to a cloud server that can be up/downgraded helped as well. All while keeping costs to about the same as the old single dedicated server.

1: https://www.drupal.org/project/advagg 2: https://www.drupal.org/project/labjs