Recently I was helping a client with a problem with VMware ESX and their datastore. The issue was that the client wanted to delete the datastore (which was empty) but the VMware Infrastructure client kept on saying "The resource is in use". It was maddening, the datastore had been completely emptied.
The fix however was simple. The client had put an ISO on that particular datastore and had told the guest OS to point to that ISO as the CD. Changing that guest to point elsewhere fixed the problem.