The other day I dumped into troubles getting an ASP.NET web application to work after migrating it from .NET 2.0 to .NET 4.0. It turned out that the problem was not bound to the .NET version but instead to the Managed Pipeline Mode settings in IIS7.
Before the migration to .NET 4.0 the application run as a .NET v2.0 Classic application pool and everything was running smoothly. The application uses a custom HttpModule for NHibernate session and transaction management, configured in web.config. All SQL CRUD stuff worked fine but the updates misfired after the upgrade.