One bottleneck hampering the widespread use of fuel cell vehicles, in particular of proton exchange membrane fuel cells (PEMFCs), is the high cost of the cathode where the oxygen reduction reaction (ORR) occurs, due to the current need of precious metals to catalyze this reaction. Electrochemists tackle this issue in the short/medium term by developing catalysts with improved utilization or efficiency of platinum, and in the longer term, by developing catalysts based on Earth-abundant elements. Considerable progress has been achieved in the initial performance of Metal-nitrogen-carbon (Metal-N-C) catalysts for the ORR, especially with Fe-N-C materials. However, until now, this high performance cannot be maintained for a sufficiently long time in an operating PEMFC. The identification and mitigation of the degradation mechanisms of Metal-N-C electrocatalysts in the acidic environment of PEMFCs has therefore become an important research topic. Here, we review recent advances in the understanding of the degradation mechanisms of Metal-N-C electrocatalysts, including the recently identified importance of combined oxygen and electrochemical potential. Results obtained in a liquid electrolyte and a PEMFC device are discussed, as well as insights gained from in situ and operando techniques. We also review the mitigation approaches that the scientific community has hitherto investigated to overcome the durability issues of Metal-N-C electrocatalysts.