Durability and performance degradation of PEM fuel cells are amongst the most critical challenges associated with this technology. Air contaminants, fuel impurities, cleansers, and some materials by which fuel cell compartments are made have been proven to have negative effects on PEM fuel cell performance. These materials can get access to anode and cathode catalyst layers, occupy catalyst sites, and deviate principal electrochemical reaction paths. Diverse studies have been conducted to date to advance the understanding of poisoning phenomena and mechanisms through which fuel cell performance is deteriorated. In addition, considerations and strategies such as subsidiary gas injection, filtration, novel tolerant catalyst layers, purification membranes, etc. have been proposed in the literature to mitigate poisoning negative effects or recover poisoned fuel cells. This paper attempts to review suspicious contaminants and impurities, poisoning mechanisms, and mitigation strategies. The present review also provides a summary on what recommended in the literature to increase the tolerance of PEM fuel cells and their catalyst layers to handle poisonous impurities. This review will though highlight research gaps in any of above-mentioned areas and make recommendations on future research contributions to the field.