Resistant pollutants like oil, grease, pharmaceuticals, pesticides, and plastics in wastewater are difficult to be degraded by traditional activated sludge methods. These pollutants are prevalent, posing a great threat to aquatic environments and organisms since they are toxic, resistant to natural biodegradation, and create other serious problems. As a high-efficiency biocatalyst, enzymes are proposed for the treatment of these resistant pollutants. This review focused on the roles and applications of enzymes in wastewater treatment. It discusses the influence of enzyme types and their sources, enzymatic processes in resistant pollutants remediation, identification and ecotoxicity assay of enzymatic transformation products, and typically employed enzymatic wastewater treatment systems.Perspectives on the major challenges and feasible future research directions of enzyme-based wastewater treatment are also proposed.