That's a lot of messages.
The answer depends on what kind of email server are you using, e.g. is it POP, Exchange, or IMAP. In any event deleting as many as you are able will surely help, but if you don't want to do that I would simply rebuild the mailbox, or each mailbox if you have more than one.
Select the mailbox, then select Rebuld from the Mailbox menu.
Always IMAP, 100% of the time for all accounts.
Rebuilding the mailbox does nothing with performance. It took 12 seconds to load the inbox when clicking on Mail before, and after rebuilding each mailbox it still taks 12 seconds to load each inbox when clicking on Mail.
Is there an option to only display 200 messages or so? The reason for the slowdown is that Mail has to retrieve 16k+ messages each time that I click on Mail. If it had to display under a thousand, I don't think the application would lag so much. Does that make sense?
One possible solution would be to organise your inbox into folders.
Its never relly good on any system to have one folder that has everything in it.
Try going to you web gui for that mail account and organise your folders and move mails from your inbox into corresponding folders for better organisation.
Several folders containing the same amount of one folder will usually load a little quicker as the folder may not be accessed to download its content unless veiwed.
So having 10 folders with organised content, and you inbox as an area thats to hold only new emails would work much much quicker with imap.
Most imap servers will only update the contents of a folder when its veiwed.