Recent studies have demonstrated that atypical antipsychotic agents, which are known to antagonize dopamine and serotonin receptors, are able to reduce T cell-driven neuroinflammation in experimental autoimmune encephalomyelitis (EAE). Given the potential of these agents to treat neuroinflammation during multiple sclerosis (MS), we compared the ability of several atypical anti-psychotic agents including risperidone, clozapine, quetiapine, and olanzapine to modify EAE to identify the most promising atypical anti-psychotic agent. Additionally, we assessed the best delivery method, therapeutic dose, serum concentration, and ability to interact with other MS therapies such as glatiramer acetate. Together these studies indicate that both clozapine and risperidone are effective immunomodulatory agents with the potential to treat neuroinflammatory diseases such as MS.