The hydrogen oxidation reaction (HOR) is the anodic reaction of hydrogen–oxygen fuel cells, which plays a decisive role in the whole-device performance. However, inexpensive crude hydrogen inevitably contains carbon monoxide (CO) impurities, and even the state-of-the-art platinum (Pt) electrocatalysts can suffer an obvious activity decrease due to the poisoning of active sites, seriously hindering the efficiency of fuel cells. Developing electrocatalysts with promoted CO tolerance necessitates the elucidation of the HOR mechanism and deep understanding of the intrinsic nature of fuel cell poisoning. To date, weakening CO adsorption or accelerating its oxidation could improve the CO tolerance of the catalyst, so it is critical to seek much more effective strategies. Based on the study of the reaction mechanism, this Review summarizes the latest progress of HOR electrocatalysts with high stability and high activity against CO poisoning from two typical theories: hydrogen binding energy theory and bifunctional theory. The strategies for enhancing the CO tolerance of catalysts are gathered, including electronic structure modulation, oxophilic sites, and dual-site construction. In addition, the applications of catalysts in practical fuel cells is outlined. In conclusion, the discussion focuses on the challenges and future outlook of CO-tolerant HOR electrocatalysts, with the objective of offering distinct perspectives on the engineering design of HOR electrocatalysts with superior CO tolerance.