Like many designers I use a font manager program (FontExplorer) to manage my collection of thousands of fonts. My problem is that the new Safari 5.1 creates an issue where fonts used to render websites are "misplaced" and a font called "lastResort" is substituted rendering pages of boxed A's making the site's pages unreadable. This was a Safari only issue, no other browser (Firefox, etc.) or program had this issue.
At first I actually thought this was a Lion install error and actually ended up reinstalling Lion from scratch a few times because of the rendering error, seems it was only a Safari issue and would only happen each time FontExplorer opened for the first time after installing Lion. Looking through Apple's Support Forums and Googling here seemed to be no end of theories on the why's and how's but no fix that actually worked for any length of time. A couple times I thought I had it but shortly after FontExplorer would open to add a font to a document I was working on and Safari would be back to boxed A's in seconds.
I finally found a solution to this frustrating issue and so far it works great. Made by someone from Insider Software (FontAgent Pro), the link goes to YouTube for a video that shows you the problem, the fix and the steps you need to take to do so. Since I am using FontExplorer I just found where FontExplorer stores my fonts and substituted the correct directory links for my situation.
‪Fix Safari 5.1 (Lion) Font Issue & FontAgent Pro.mov‬‏ - YouTube
I hope this helps as this was a super frustrating part of my upgrade process to Lion It almost made me switch back to Snow Leopard and it definitely delayed me from upgrading the other systems in my office.