How do you tune your MySQL database as the size of your data set grows?

I've been using a variety of web applications that use MySQL as a data store. Recently, as one of those has become more popular in my work, the amount of data that its storing in the database has grown exp开发者_运维问答onentially, but I'm still using the default installation of the database.

Are there any particular areas where one could suggest improvements in the database when changing the codebase of the application is not an option?

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If the apps aren't creating new persistent tables, switching from MyISAM to InnoDB and adding indexes on frequently-queried columns might help.