Hi jefftate,
There's a difference between deleting manifest files and deleting some files in the manifest cache. As Richard recommended, and I fully concur, you definitely do
not want to delete or modify or do anything with the manifest files - that is clear from a multitude of sources including the one listed above. The latter, however, can be done to some degree but be careful you follow the instructions exactly and word-for-word and
do ONLY what is suggested and nothing more. You cannot just delete it - you can only follow the instructions that follow to help clear some of it. From what I understand, this doesn't free up as much space as you might hope, but it does help a bit. Also, if I understand correctly, it will soon recreate itself so some have suggested it is somewhat pointless in the long term - but if you want to try you can do so at your own risk. I would most certainly create a system restore point before starting and perhaps even do a full backup if yours isn't current and sufficiently up-to-date.
Here's the best article I found on the procedure:
Microsoft Certified Exchange AD Professional: ManifestCache Windows 2008 and Vista. Please note that it fails to mention that at the end you need to also input the command net start trustedinstaller so make sure to add that if you do this.
Here's another article from the Microsoft Answer Forums by a Microsoft Support moderator and marked as an answer by a Microsoft Systems Engineer that essentially says the same thing, but the post is poorly formatted so it's hard to read (and it also forgets to mention the net start trustedinstaller step):
Can I delete the file C:\Windows\winsxs\ManifestCache to increase disk space?. I include it not because it provides much additional information (though it would be good to review it so you read all that's relevant before starting), but because it provides additional support for the above procedure as valid and acceptable (provided it is done properly and EXACTLY according to the instructions).
I hope this helps.
Good luck!