In this chapter, we review data in support of the concept that immune system dysregulation is the most plausible explanation that reconciles gene by environmental interactions in schizophrenia. Early investigations of this topic demonstrated aspects of aberrant activation of humoral immunity, including autoimmunity, associated with schizophrenia, whereas current research efforts have expanded this theme to include elements of innate immunity. Advances in our understanding of inflammation and molecules of both the adaptive and innate immune system and their functional roles in standard brain physiology provide an important context by which schizophrenia might arise as the result of the coupling of immune and neurodevelopmental dysregulation.