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. The key objectives of this dissertation are to develop nitritation-anammox process to treat wastewater with low-nitrogen strength, understand the fundamental microbiology, and optimize its operation through experimental studies and mathematic modeling. Chapter 2 showed that the nitritation-anammox process has been successfully developed in an upflow membrane-aerated biofilm reactor, where pure oxygen was delivered via gas-permeable membrane module. Chapter 3 demonstrated that hybrid anaerobic reactor (HAR) could be an effective pretreatment method to provide a relatively low COD/N ratio for nitritation-anammox reactor. In Chapter 4, a novel mathematical model has been proposed to evaluate the minimum DO requirement for the nitritation-anammox reactor to achieve the maximum TN removal under various COD/N scenarios (controlled by HRTHAR). Chapters 5 and 6 designed an OsAMX system by linking nitritation-anammox to forward osmosis to remove the reverse-fluxed ammonium while using ammonium bicarbonate as a draw solute. The microbial community structures and dynamics, spatial distributions in these bioreactors were characterized by high-throughput sequencing and fluorescent in situ hybridization techniques. The studies in this dissertation have demonstrated that nitritation-anammox process is a promising alternative for sustainable mainstream treatment with the appropriate pretreatment approach and operation optimization. / PHD / Eutrophication due to the discharge of excessive N and P concentrations into water bodies is pervasive in the United States. The increasingly stringent nitrogen discharge criteria with minimized energy consumption and carbon footprint has become a great challenge for wastewater treatment facilities. Compared with nitrification-denitrification process, nitritation-anammox process is a cost-effective technology because it significantly decreases oxygen and organic carbon consumption. In Chapter 2, the nitritation-anammox process has been demonstrated for the first time to treat low nitrogen strength wastewater in an upflow membrane-aerated biofilm reactor with pure oxygen supply. The membrane aeration with upflow pattern have shown to promote oxygen mass transfer and biomass retention through the formation of biofilm and granules. Chapter 3 demonstrated that hybrid anaerobic reactor could be an effective method to pre-remove most organic matters for nitritation-anammox reactor so that anammox and ammonia-oxidizing bacteria can outcompete heterotrophic organisms. A mathematical model has also been developed in Chapter 4 to evaluate the effects of COD/N ratio on minimum DO requirement and microbial distributions in the nitritation-anammox reactor. Chapters 5 and 6 investigated the potential application of nitritation-anammox to remove reverse-fluxed ammonium leaked by forward osmosis using ammonium bicarbonate as a draw solute. These studies collectively showed that nitritation-anammox process could create opportunities for achieving sustainable wastewater treatment with minimum input of resources.