I recently wasted several hours (not to mention fried brain cells) trying to figure out why a website was returning 404 errors for all the WebResource.axd requests.
Searching the Internet revealed several possible causes and fixes, such as changing the Application Pool to Classic mode (not an option; integrated mode was required), ensuring the handlers were registered (they were), and praying (let me down again, God).
This was especially problematic, because most of the people experiencing this issue were getting a 404 on both WebResource.axd and ScriptResource.axd, whereas I was only missing the former.
Fortunately, by accident I stumbled on this thread on Stack Overflow: WebResource.axd - works on one computer; gives 404 on another.
The original poster discovered that the server times between the two machines were different, and correcting the discrepancy resolved the issue.
I never would have even thought to look at the server time, but glancing down at the clock, sure enough it was set to October 2010! Updating the time to current immediately fixed the issue.
So if you are at a loss and have tried everything else, remember to check your clock!
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SelAromDotNet
Josh loves all things Microsoft and Windows, and develops solutions for Web, Desktop and Mobile using the .NET Framework, Azure, UWP and everything else in the Microsoft Stack.
His other passion is music, and in his spare time Josh spins and produces electronic music under the name DJ SelArom.