For one, they mess up with your browser history and limit your ability to bookmark a particular page as almost all contents are loaded "in-page". The other disadvantage I see is the in-ability of custom scripts to access the site and extract information.
Development wise, you introduce a sense of uncertainty into your web-page where when your page looks like it has completed loading, more data is still being AJAX'ed. This may lead to difficulties in maintainability.
Though there are a lot of benefits of using AJAX, the main being better user experience, for scripters, this is a blocker.
- A parallel web-service based interface would help those who are armed with Perl or Python to extract useful information at a jiffy
- A simplified web alternative will cater to the needs of the cellphone user or the average scripter.