Polymer electrolyte membrane water electrolysis (PEMWE) has been regarded as a promising technology for renewable hydrogen production. However, acidic oxygen evolution reaction (OER) catalysts with long‐term stability impose a grand challenge in its large‐scale industrialization. In this review, critical factors that may lead to catalyst's instability in couple with potential solutions are comprehensively discussed, including mechanical peeling, substrate corrosion, active‐site over‐oxidation/dissolution, reconstruction, oxide crystal structure collapse through the lattice oxygen‐participated reaction pathway, etc. Last but not least, personal prospects are provided in terms of rigorous stability evaluation criteria, in situ/operando characterizations, economic feasibility and practical electrolyzer consideration, highlighting the ternary relationship of structure evolution, industrial‐relevant activity and stability to serve as a roadmap towards the ultimate application of PEMWE. The large‐scale application of polymer electrolyte membrane water electrolysis (PEMWE) is suffering from long‐term stability challenges in anodic oxygen evolution reaction (OER). This review provides a thorough discussion of degradation mechanisms, catalyst design principles and future research opportunities to serve as a cornerstone for overcoming the dilemma in acidic OER stability and achieving the industrialization of water electrolysis.