Don't pass requests for certain file types to WordPress for 404 handling.
If you use the pretty permalinks feature of WordPress, any request that doesn't match to a file on the server will be passed to WordPress for handling. This results in 404 hits having more load on your server than a traditional 404 request. In particular it can be a problem if a directory of images is moved or missing, as each page load request might spawn dozens of 404-ing image requests - effectively increasing your server load by a multiplier.
This plugin allows you to set a list of file extensions that you do not want WordPress to handle 404s for. By default, it includes a list of media types, but you may want to adjust this to suit your needs.