`lsof` is indeed your best bet. The fastest and easiest way would be this :-

    sudo lsof /Volumes/myDrive

It can take a couple minutes to run, but once it's complete, it gives you a list of open files on the disk. The output will look something like this:

    COMMAND    PID  USER   FD   TYPE DEVICE SIZE/OFF  NODE NAME
    mds         89  root   19r   DIR   52,3      432     2 /Volumes/Photos
    mds         89  root   23r   DIR   52,3      432     2 /Volumes/Photos
    Finder     681 alans   14r   DIR   52,3      432     2 /Volumes/Photos
    QuickLook 2158 alans    9r   REG   52,3  1141591 78651 /Volumes/Photos/_tmp_iphone_10_backup/APC_1546.JPG  

In this case, it's the `QuickLook` application that has a file open. Closing the application directly is the best way to fix the issue. However, that's not always possible. For example, QuickLook doesn't show up as an application you can get to in the Dock. 

If you can't close the application manually, you can use the `kill` command to terminate it from the command line. To do that, use the `PID` from the second column as the ID to kill. From the above example, it would be:

    kill 2158

Note that sometimes that doesn't work and a more aggressive form of `kill` must be used. Here's a series of escalating aggressiveness (using the example PID of 2158):

    kill 2158
    sudo kill 2158
    sudo kill -INT 2158
    sudo kill -KILL 2158

You should be able to eject the disk once the process/application has been killed. 

One final note, `lsof` can take a minute or two. It can also hang, but you should give it at least a few minutes before you decide that's what happened. 

Also, sometimes the base command `sudo lsof /Volumes/myDrive` won't find anything. If that happens, try adding the `+D` argument (i.e. `sudo lsof +D /Volumes/myDrive`). That will do a top down scan of the disk. It'll take longer, but it should pick up anything that's causing the disk to be un-ejectable.

(_Hat tip to [Alec Jacobson's post](http://www.alecjacobson.com/weblog/?p=649) for extra details._)