Schizophrenia is a chronic debilitating neuropsychiatric disorder with a complex genetic contribution. Although multiple genetic, immunological and environmental factors are known to contribute to schizophrenia susceptibility, the underlying neurobiological mechanism(s) is yet to be established. The immune system dysfunction theory of schizophrenia is experiencing a period of renewal due to a growth in evidence implicating components of the immune system in brain function and human behavior. Current evidence indicates that certain immune molecules such as Major Histocompatibility Complex (MHC) and cytokines, the key regulators of immunity and inflammation are directly involved in the neurobiological processes related to neurodevelopment, neuronal plasticity, learning, memory and behavior. However, the strongest support in favor of the immune hypothesis has recently emerged from on-going genome wide association studies advocating MHC region variants as major determinants of one's risk for developing schizophrenia. Further identification of the interacting partners and receptors of MHC molecules in the brain and their role in down-stream signaling pathways of neurotransmission have implicated these molecules as potential schizophrenia risk factors. More recently, combined brain imaging and genetic studies have revealed a relationship between genetic variations within the MHC region and neuromorphometric changes during schizophrenia. Furthermore, MHC molecules play a significant role in the immune-infective and neurodevelopmental pathogenetic pathways, currently hypothesized to contribute to the pathophysiology of schizophrenia. Herein, we review the immunological, genetic and expression studies assessing the role of the MHC in conferring risk for developing schizophrenia, we summarize and discuss the possible mechanisms involved, making note of the challenges to, and future directions of, immunogenetic research in schizophrenia. (C) 2012 Elsevier Inc. All rights reserved.