Most ASP.Net developers quickly learn that web.config file settings percolate from the top down.  This is commonly used to provide global configuration for a single web application, but it's pretty easy to forget that web.config settings can be inherited across different virtual directories.

For example:

1) Create a website in IIS.
2) Create a virtual directory for a second site underneath the IIS website.
3) Reference a type in the web.config for site #1, such as in a HttpHandler block.
4) Unless the second site has the type referenced in #3 (or it is in the GAC), second site will now immediately throw an exception, "Cannot load type xxx.xxx.xxx".

In web.config #1
<httpHandlers>
   <add verb="GET" path="*.css.ashx" type="NFC.PublicWeb.UILogic.PathResolver,NFC.PublicWeb"/>
</httpHandlers>

This issue is caused because every virtual directory underneath the top-level website is inheriting settings from the top-most web.config.  Many of these inherited settings would go unnoticed, but as soon as the child virtual directory hits something it can't handle, it immediately throws a show-stopping (as all config errors are) exception.

Quick Solution?
Wrap application specific blocks of code in the LOCATION tag.  Obviously this must be used judiciously, but it's a useful fix to a sneaky problem.