So I have an external HDD that I have all my projects on. I have gone to Options, Global and changed the drive to "E" where my projects reside, but I can't open a project. I have been having problems with the HDD being seen or recognized, but once I get it in sight on Windows Explorer, I don't have a problem. Can someone walk me thru this. I also have the Audio Data path pointing to "E" too. I don't know what is going on. Thanks.

Maybe bad cable, external power supply, corrupted or failing hard drive.

Is there an error message? Is it a powered drive, meaning you have to plug it into a wall outlet? 

Just a guess, but it sounds like the external drive may be going to sleep. Well, actually it'd be the USB port that goes to sleep. Listing files via Explorer wakes it up. Try disabling standby mode for the USB ports. Go into Device Manager, scroll down to the USB hubs, right-click on each one and select Properties, then go to the Power Management tab and uncheck the "allow turning off this device" option.

And one would hope that that is not the ONLY place you have stored your projects. 

Best to work with a nice fast internal drive and use the externals for backup only. To many things that could happen like what Dave just said about sleep mode etc. 
And windows will not assign the same drive letter each time you hook it up. If you plug in your camera, USB stick or any other storage it will assign that same letter there too. 

 Thanks all. I think it went to sleep. This is the problem I have with it more frequently than not. I do, have a backup for this, but really wanted to get this back up. I will remedy the sleep problem in the device manager. It is powered, by the way, and there is no error message. I think I will "safely remove hardware and eject media" before I shut down. I tried this three times (after I got it up again) and it worked every time, meaning, when I started up, it was ready to work. So, I think I should do this on a regular basis, as I have been meaning to do so, but keep forgetting. What was odd, was, after I got it up and running, I still could not open projects. Must have been some weird glitch. Anyhow, it is working great now. Thanks to all of you for your help. Here is what I take away from this. Get a new external HDD, manage USB power for "no sleep" mode, and eject media before shut down (without physically removing the thing).