I have an intermittent problem that just started showing up several days ago. I am running 11.10 and all updates are current.
I first saw the symptom with a custom version of the "Home" nautilus-home.desktop file I created in ~/.local.share/applications. I added a few static shortcuts to specific folders. What I found was, clikcing the icon once would open up my home folder, but after closing that nautilus window, clicking the icon again did nothing (did not even show icon backlight animation). However, I could right click on the same icon and access my short cuts as many times as I want. Symptom persisted until restarting lightdm. Just yesterday I saw the same sort of symptom happen with a custom launcher I created for a chromium-borwser to open a specific URL (with a few short cuts to other URLs). Click the icon - it works once. Then never again. Right click the icon and I can use the short cuts over and over - no problem.
Note - at one point I assumed I might have a problem with my custom .desktop file, so I did a test by removing my custom nautilus-home.desktop. However, even after restarting lightdm, and verifying the home icon was the standard one from /opt/share/applications (all my custom shortcuts were gone) I saw the same symptom re-appear - it runs once and then not again until restarting lightdm.
It seems to be intermittent and seems to move between various launchers. Not sure what to do or even what background data to gather.
Attempt to improve question after the first answer:
I tried the following: 1) remove all custom launchers 2) reboot 3) add custom lauchers back 4) reboot 5) attempt to use .... still have "runs once and never again" symptom with several launchers