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Frequently when WP is going crazy it is because someone is using wp-cache but doesn't have it installed properly. It then generates more work for the server than if it were not there. That probably applies to 8 out of 10 wp-cache installs I have looked at. As a rule, the cache directory doesn't exist, else it and/or the WP config file have the wrong permissions.
Otherwise, although WP has some of the sloppiest code I have seen for the way it makes database calls, the biggest issue seems to be how well the server is configured. Credit to my techies because I know very little about that end of things, but for 3+ years I have had multiple instances of WP and other reputed hogs running on very ordinary boxes without any problems.
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