I tried the usual stuff, and my exact scenario ended up being described a post in the MSDN forums. Its answer worked for me, despite my environment (VS2008, .NET 3.5) being more modern:
Here are the steps I followed (basically a summary of the link above -- "ASPNET" being significant because that's the user running the IIS instance on my development box):
- Close VS
- Shutdown IIS
- Add ASPNET to the local Administrators group
- Start IIS
- Start VS and successfully debug ASP.NET webapp
- Close VS
- Shutdown IIS
- Remove ASPNET from the local Administrators group
- Start IIS
- Start VS and continue debugging ASP.NET webapp without error
My development workstation's security settings/situation is regularly managed by our security folks here, so something must have upset my ASP.NET/IIS/etc environment.