Schizophrenia and bipolar disorder are serious neuropsychiatric disorders of uncertain etiology. Recent studies indicate that immune activation may contribute to the etiopathogenesis of these disorders. Numerous studies in animal models indicate that the mucosal microbiome may influence cognition and behavior by altering the functioning of the immune system. It is thus likely that the microbiome plays a role in human psychiatric disorders. The study of immune alterations and the microbiome in schizophrenia and bipolar disorder is in its infancy. Two recent investigations of the oro-pharyngeal microbiota in schizophrenia found differences between cases and controls. Other studies have found increased gastrointestinal inflammation in schizophrenia and bipolar disorder based on measures of microbial translocation. Several studies have also found an association between the receipt of antibiotics and an increased incidence of psychiatric disorders, perhaps due to alterations in the microbiome. Studies to characterize the intestinal microbiome of individuals with these disorders are in progress. The ultimate test of the role of the microbiome and immune-mediated pathology in schizophrenia and bipolar disorder will come from clinical trials of therapeutic agents which alter gut microbiota or gastrointestinal inflammation. The successful development of such modalities would represent a novel strategy to prevent and treat serious psychiatric disorders.