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Purpose of Review: The immune system is of pivotal importance with regard to the development and maintenance of mental illness. Aberrant cytokine levels are significant immune markers, and research is increasingly focusing on the complement system and the gut-brain axis. The efficacy and safety of immunomodulatory interventions are currently the subject of clinical studies. Hence, this review is timeline and relevant to evaluate the latest evidence on the clinical value of immunomodulatory treatments from studies over the past 18 months in schizophrenia, bipolar disorder and unipolar depression., Recent Findings: While conventional psychotropic drugs (antidepressants, antipsychotics, lithium) appear to have immunomodulatory adverse effects, antibiotics (minocycline), nonsteroid anti-inflammatory drugs (celecoxib) and anti-inflammatory therapeutics in particular are the subject of ongoing clinical trials. Integrative medical interventions such as nutritional supplements (e.g., N-acetyl-l-cysteine, polyunsaturated fatty acids) and exercise interventions (e.g., running, yoga) are being evaluated for their immunomodulatory effects and clinical value., Summary: No evidence-based recommendation can be made for the immunomodulatory treatment of depression, although celecoxib appears to be more effective than minocycline and omega-3 fatty acid. N-acetylcysteine (NAC) may be beneficial for the treatment of bipolar and schizophrenia disorders. However, further translational research is required to confirm these findings., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)