There is a little known issue with query cache which can cause issues when the cache is larger then 64 megabytes. It can cause mysql to lock up for several minutes when the cache is invalidated. The MySQL guys gave a presentation at DrupalCon Boston about this. If anyone wants more info, go to drupalcon.org and search for the MySQL presentation, or post here and I will post a link in response. The short and sweet is: Use query cache, put don't set it to more then 64M.
Andy