Major recent discoveries have bringing out a revised definition of paraneoplastic neurological syndromes (PNS), bringing out the concept of antibody-mediated neurological disorders, triggered or not by cancer. Classification of these diseases is not based anymore on the clinical pattern or an underlying tumor, but on the location of the targeted antigens. Indeed, evolution, response to treatment, and pathophysiology are radically different according to the associated antibodies. In some patients with newly described antibodies targeting cell-surface antigens, humoral immunity seems to play a direct role and a dramatic improvement is observed with immunomodulator treatments. In these patients, an associated tumor is less frequent. Conversely, patients with antibodies directed against intracellular targets are, in most cases, characterized by a high degree of irreversible neuronal death mediated by cytotoxic T-cells and do not improve after immunomodulator treatments. In these patients, an associated tumor is highly frequent and must be cured as soon as possible. A third group of patients can be identified with anti-GAD65 and anti-Amphiphysin antibodies. In patients with these antibodies, the efficiency of immunomodulator treatments is less clear as well as the type of immune response that could be a mix between humoral and cellular. In this last group, the antigen is intracellular, but patients may improve with immunomodulator treatments and associated tumors are rare. Thus, identification of associated antibodies should be prompt and the treatment guided according the identified antibody. Mainstream of treatment include the quest of a tumor and its cure. Immunotherapy must be promptly initiated, targeting humoral, or cellular immune response, or both, according to the associated antibodies. Furthermore, in some situations such as Lambert-Eaton Myasthenic Syndromes and Stiff-Person Syndromes, symptomatic drugs can be useful to control the symptoms.