OK, at least they're enabled :-) I'm not a DBA, but have hit IO issues with my MYISAM/MYSQL database many times myself.<p>1) Have you run Mysqltuner? If not, 
wget <a href="http://mysqltuner.com/mysqltuner.pl" rel="nofollow">http://mysqltuner.com/mysqltuner.pl</a>
chmod to executable
and execute it. I find it rather helpful.<p>2) Are you indexing every field that is part of any WHERE statement (at least for the big tables)?<p>3) Have you run EXPLAIN on the original query? (Suggested by someone else in this thread, and a critical question.)<p>4) Is the slow_query_log enabled, and are you sure about which query is causing the slowdown?<p>5) Have you tried tools like MySQL Administrator, which lets  you monitor connections, threads, keys, queries, etc, in realtime?