In many applications, MyISAM can be used successfully if the proportion of write operations is only a small fraction of the read operations. As the tables grow, the 4 GB limitation in the key_buffer size caused performance issues and other strategies. Wait… did I miss something… From a recent comment to a post from Matt I re-read the MySQL documentation and realized I missed a big change that occurred with versions 5.0.52 and 5.1.23 (http://dev.mysql.com/doc/refman/5.1/en/server-system-variables.html#sysvar_key_buffer_size)
As of MySQL 5.1.23, values larger than 4GB are allowed for 64-bit platforms
So, key_buffer as large or even larger than 32 GB are possible. That is an important design consideration that needs to be taken into account when tuning a database.