I just installed Visual Studio 2010 yesterday. As part of that I installed VSTO 4.0. Now when I run any Office application, my VSTO 3.0 addins fail to load. The error in the event log is

Customization URI: file:///H:/PathToMyAddin/MyAddin.vsto Exception: Customization does not have the permissions required to create an application domain.

***** Exception Text ******* Microsoft.VisualStudio.Tools.Applications.Runtime.CannotCreateCustomizationDomainException: Customization does not have the permissions required to create an application domain. ---> System.Security.SecurityException: Customized functionality in this application will not work because the administrator has listed file:///H:/PathToMyAddin/MyAddin.vsto as untrusted. Contact your administrator for further assistance. at Microsoft.VisualStudio.Tools.Office.Runtime.RuntimeUtilities.VerifySolutionUri(Uri uri) at Microsoft.VisualStudio.Tools.Office.Runtime.DomainCreator.CreateCustomizationDomainInternal(String solutionLocation, String manifestName, String documentName, Boolean showUIDuringDeployment, IntPtr hostServiceProvider, IntPtr& executor) The Zone of the assembly that failed was: MyComputer

It seems like like maybe this is due to it trying to load different version of .NET is the same process/AppDomain. However the error would indicate it's some sort of permissions issue.