The nitritation–anammox process is an efficient and cost‐effective approach for biological nitrogen removal, but its application in treating mainstream wastewater remains a great challenge. Mainstream nitritation–anammox processes could create opportunities for achieving energy self‐sufficient, or energy‐generating water resource recovery facilities. Significant advancements have been achieved via pilot‐ and full‐scale trials to overcome the major obstacles under mainstream conditions, such as repression of nitrite‐oxidizing bacteria, limiting the overgrowth of denitrifiers, and effective selection and retention of ammonia‐oxidizing bacteria and anammox bacteria. This review paper intends to provide a detailed update of research progress on mainstream nitritation–anammox processes, discuss metabolic interactions, and examine major challenges and possible solutions towards the future development.