Autoimmune mechanisms causing dysfunction of the brain are increasingly recognised and brought about a paradigm shift in neurology and psychiatry. Identification of numerous pathogenic auto-antibodies against neuronal tissue resulted in unprecedented diagnostic and therapeutic opportunities. Current clinical and experimental data show that diverse neuropsychiatric abnormalities may be the sole symptoms of brain autoimmunity. Affected patients are at risk that such treatable etiologies are overlooked as rheumatic or psychiatric disorders. In some patients the diagnosis can be made by detection of specific auto-antibodies directed against neuronal or glial surface proteins. These epitopes include voltage-gated potassium channels or glutamate receptors, but also novel antigens not yet tested for autoimmunity, such as cell adhesion molecules or enzymes. The identification and recombinant production of disease-defining human monoclonal autoantibodies from these patients now allow detailed analyses of the pathogenic effects, of signaling cascades leading to neuropsychiatric symptoms and potential triggers of autoimmunity. It has become clear that the perpetual discovery of novel antibodies will continue and ultimately result in a better understanding of pathological mechanisms and therapies in patients with impairment of memory, cognition, affect and mood.