The evidence to date, coupled with advances in immunology and genetics has afforded the field an unparalleled opportunity to investigate the hypothesis that a subset of patients with schizophrenia may manifest an immunophenotype, toward new potential diagnostics and therapeutics to reduce risk, alleviate symptoms, and improve quality of life in both at-risk populations and patients with established schizophrenia. In this paper, we will first summarize the findings on immune dysfunction in schizophrenia, including (1) genetic, prenatal, and premorbid immune risk factors and (2) immune markers across the clinical course of the disorder, including cytokines; C-reactive protein; immune cells; antibodies, autoantibodies and comorbid autoimmune disorders; complement; oxidative stress; imaging of neuroinflammation; infections; and clinical trials of anti-inflammatory agents and immunotherapy. We will then discuss a potential mechanistic framework toward increased understanding of a potential schizophrenia immunophenotype. We will then critically appraise the existing literature, and discuss suggestions for the future research agenda in this area that are needed to rigorously evaluate this hypothesis.