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Accumulating evidence suggests the association of systemic inflammation as well as glia-mediated neuroinflammation with cognitive and affective behavioral deficits in psychiatric disorders. Heterogeneities of glial cells including both microglia and astrocytes contribute to their varying sensitivities to the same physiological and pathological signals in different brain regions, which underlies their functional relevance for mental disorder development. My research focuses on glia-related mechanisms in psychiatric disorders by using genetic, biochemical and neuroimaging methods to study psychiatric patients and animal stress models. Here, I present our recent findings on this research. In animal research, we study chronic stress-induced glial activation and involvement of glial subpopulations and their target genes in psychiatry-like behaviors using neuroinflammatory models. In clinical research, we analyze various omics data along with patients’ clinical scores on cognitive and pathophysiological functions, to understand the immune-mediated mechanisms on disease onset, development and treatment response of schizophrenia. Our conclusion is that immune cells and genes play pleiotropic roles in shaping the brain structural and functional connectivity that is pivotal for schizophrenia.