We first provide a brief overview of the leading mechanisms speculated to cause monolayer degradation along with proposed solutions to decrease the degradation rate, followed by experimental results obtained in buffer and raw undiluted serum at 4 ˚C and 37 ˚C. Several of the observed results are surprising, revealing that short term solutions to improving sensor longevity over several hours may actually increase sensor degradation during multi-day operation. The results and underlying insights on mechanisms not only push forward fundamental understanding of stability for self-assembled monolayer chemistry, but demonstrate an important milestone for continuous electrochemical aptamer biosensors and other biosensors that rely on molecular self-assembly on gold substrates, such as immunosensors, peptide-based sensors, and other electrochemical nucleic acid sensors.