Interesting write up by James at Incsub on how they handle scale on edublogs. Some good advice although a little light on specifics, a good starting point for research.
Varnish is a state-of-the-art, high-performance HTTP accelerator (reverse proxy). Varnish is designed by a BSD kernel developer to make full use of BSD / Linux kernel's ability to manage memory. It is extremely fast, up to 10 - 20 times faster than squid.