Driven by energy neutral/positive of wastewater treatment plants, significant efforts have been made on the research and development of mainstream partial nitritation and anaerobic ammonium oxidation (anammox) (PN/A) (deammonification) process since the early 2010s. To date, feasibility of mainstream PN/A process has been demonstrated and proven by experimental results at various scales although with the low loading rates and elevated nitrogen concentration in the effluent at low temperatures (15–10 °C). This review paper provides an overview of the current state of research and development of mainstream PN/A process and critically analyzes the bottlenecks for its full-scale application. The paper discusses the following: (i) the current status of research and development of mainstream PN/A process; (ii) the interactions among aerobic ammonium-oxidizing bacteria, aerobic nitrite-oxidizing bacteria, anammox bacteria, and heterotrophic bacteria; (iii) the suppression of aerobic nitrite-oxidizing bacteria; (iv) process and bioreactors; and (v) suggested further studies including efficient and robust carbon concentrating pretreatment, deepening of understanding competition between autotrophic nitrogen-converting organisms, intensification of biofilm anammox activity, reactor design, and final polishing.