How to optimize the my.cnf of a MySQL server that mixes InnoDB and MyISAM tablespaces?
One of the most important variables for InnoDB is innodb_buffer_pool_size. This is the amount of memory allocated to load tablespace information for InnoDB only.

Since you are mixing MyISAM and InnoDB, you will need to find a good balance between key_buffer_size (for MyISAM indexes) and innodb_buffer_pool_size (for InnoDB reads). 

In general, you want to fit your entire data into memory if possible, as disk reads are (obviously) very expensive.

You didn't mention which MySQL version you are running, but I would recommend reading through the documentation of the appropriate version for tuning InnoDB for more detailed information.