you definately want to test with and node_access module like organic groups if you intend to use one in production. the presence of this sort of module adds some complexity to some key queries. any large php site that dreams of being 'google fast' has to use an opcode cache application. see http://drupal.org/node/2603. this is the biggest bang for the buck improvement you can make. on the downside, it is rumored to segfault under certain conditions and i saw that a bit myself when uploading files into drupal.
2) We would like implement a better caching strategy. We are aware of several implementations. Once the site becomes an active community of posters caching become less useful. -We are planning on using Jeremy Andrews caching patch for testing. -We would welcome other suggestions.
I don't think there is a caching patch in the queue. just test with HEAD Drupal and you have our best effort. the traffic pattern matters a lot here. lots of registered users yields a far heavier load than lots of anon users (this is the slashdot scenario). Drupal's highest performing cache setting is called 'Loose'. Any high traffic site will want this, so i see no reason to test otherwise. At one time, we thought that there must be a bug in its implementation because drupal.org was not experiencing a good cache hit ratio. In the end, I think we saw that some misbehaved crawlers and hosts were slamming the site and requesting many obscure pages not in the cache. One of them was AskJeeves! Lots of discussion starting with this post: http://lists.drupal.org/archives/infrastructure/2005-05/msg00123.html and conturing into the next month ... This sort of optimization really requires drupal knowledge and not just 'optimization experience.'
3)MySQL specific optimizations- John Paul Ashenfelter is a very experienced performance tuner and is heading up the scalability project. -We are interesed in MySQL cache optimizations. -In particular MySQL replication topologies as well as using the Memory table type for some of the problematic data. -If you have experience tuning large or high performance sites with MySQL we would appreciate your insight.
i recently enabled the mysql cache on some of my sites and saw a big boost. i encourage folks to read an intro at http://dev.mysql.com/tech-resources/articles/mysql-query-cache.html. once you've enabled this, i think the DB becomes a minor performance concern. Of course that depends a lot on what modules you use and how much data you have (thousands of terms, thousands of users, etc.)