Anti-NMDAR encephalitis is a newly characterized syndrome with a progressive, predictable clinical course and the possibility of effective treatment. Accurate and timely diagnosis is critical to selection and implementation of treatments, and optimal patient outcomes. Outcomes are improved with early diagnosis via indirect immunofluorescence or cell-based assays, and the rapid and appropriate administration of immunosuppressant and anti-psychotic therapies. Three possible scenarios accounting for the immunopathogenesis of anti-NMDAR encephalitis are presented, with the most probable one being that of paraneoplastic autoimmunity. Future efforts in this disorder should focus on elucidating the mechanisms that contribute to initiation of this antibody response, as well as exploring the role of tumors, infectious triggers and immune-reactivation. Finally, accessible tools need to be developed that allow for reliable identification of specific antibody markers against synaptic proteins.