I had a nearly empty datastore in one of my vSphere clusters that I wanted to destroy so I could steal some of the LUNs to grow a different datastore. I migrated all machines and files off the datastore, it was completely empty, but I kept getting an error from vCenter saying it was unable to delete the datastore because the resource was in use. I eventually discovered that a VM in the cluster had its CD-ROM connected to one of the ISOs that I had moved off the datastore. Disconnected the CD-ROM and I was good to go.