Obviously, uploading a sketch.
I also have multiple issues like that.
I have a feeling there is some 'gray area' somehow related to MEGA bootloader.
Sketch is complicated enough, with Adafruit datalogger shioeld, LCD shield and QuadRAM shield.
It might be working perfectly well for days, than something happens and you cannot upload anymore.
Sometimes uploading another simple sketch helps, sometimes it does not.
My common impression is that Arduino MEGA 2560 is very unstable board, hardly useful for anything more complicated than blinking LEDs
BTW, Ard DUE is even worse.