The function of pro-inflammatory cytokines and chemokines in brain injury and autoimmune diseases has been long recognized. There is however, a significant lack of information regarding the role of constitutively expressed immune genes in the normal brain. The current evidence points to the involvement of certain cytokines and major histocompatibility complex (MHC) molecules in synaptic function and plasticity. Furthermore, constitutively expressed chemokines in neurons provide an additional indication of a role for these molecules in neural function. In addition, clinical data suggests a dysregulation of immune genes in the cerebrospinal fluid of psychiatric patients who have neither brain injury nor autoimmune diseases. This review will discuss recent data indicating a role for immune genes in synaptic stability and will also discuss the implications for specific brain functions involving mood and cognition.