Mental, neurological and substance use disorders (MNS) constitute 13% of the global disease burden, surpassing both cardiovascular diseases and cancers. Major depressive disorder (MDD) and schizophrenia are among the three most disabling MNS illnesses worldwide. The contribution of chronic inflammation to major mental disorders has received increased attention in the last decade, which revealed a host of pharmacological targets. Multiple recent reviews clearly demonstrate that schizophrenia is associated with a dysregulation of immune responses, as reflected by the observed abnormal profiles of circulating pro- and anti-inflammatory cytokines in affected patients. Moreover, some anti-inflammatory drugs have shown their effectiveness in the treatment of schizophrenia. Anti-inflammatory drugs have shown effectiveness in major psychiatric disorders, especially major depressive disorder (MDD) and schizophrenia. Four major classes of anti-inflammatory drugs have been studied to date: polyunsaturated fatty acids (PUFAs), cyclooxygenase (COX) inhibitors, anti-TNFalpha and minocycline. We discuss the positive results of PUFAs in MDD, the mixed results for COX-2 specific inhibitors and minocycline in schizophrenia, and the positive preliminary data on aspirin and n-acetyl-cysteine. Adjunctive aspirin was shown to significantly improve psychotic symptoms in schizophrenia, but only two randomized controlled trials were carried out to date. Anti-TNFalpha showed also important effectiveness in resistant MDD with blood inflammatory abnormalities, which may highlight potential biomarkers of interest. A number of anti-inflammatory drugs are available as adjunct treatment for treatment-resistant patients with MDD or schizophrenia. If used with caution, they may be reasonable therapeutic alternatives for resistant symptomatology.