Proton exchange membrane fuel cell (PEMFC) is deemed as an efficient and eco-friendly technology with high energy conversion rate and low start-up temperature. Large-scale commercialization of PEMFC, however, has been severely retarded by insufficient power, short life span and high costs of Pt-based catalysts. Substantial progress on cost-effective single-atom catalysts (SACs) have witnessed significant improvements of sluggish cathodic oxygen reduction reaction (ORR) and anodic hydrogen oxidation reaction (HOR) for PEMFC. Nevertheless, practical application of SACs is plagued by degradation issues even though numerous studies said that SACs are comparable or even surpass Pt/C catalysts. The resulting question, “What is the Achilles’ heel of SACs towards practical PEMFC application?” is herein the centerpiece of this review. Recent advanced development of SACs towards PEMFC devices, covering HOR and ORR is presented from fundamental insights to practical application. In view of the requirement for efficient PEMFC, the structure design and regulation of SACs are targeted to improve the performance and service life of PEMFC. This review points out the existing issues and design principles of SACs, which are expected to pave the way for efficient PEMFC application.