Are you using ASP.NET MVC or System.Web.Routing?
Do you have something like
routes.IgnoreRoute("{resource}.ashx/{*pathInfo}");
in your function RegisterRoutes()in your instance HttpApplication?
Keep in mind that the Visual Studio server environment executes all requests through a managed pipeline.
httpHandler system.web Web.config? ( IIS7 system.webServer, , Cassini.)