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.