Glutathione is the brains principal antioxidant. There is evidence of oxidative stress and alterations of free radical defences in autism, depression, bipolar disorder and schizophrenia. Established antidepressants, antipsychotics and mood stabilisers have a role in ameliorating oxidative stress. N-acetyl cysteine (NAC) is a precursor of glutathione. NAC increases neurogenesis, neuronal sprouting and reverses animal models of oxidative stress, and raises peripheral glutathione levels. NAC raises peripheral and brain glutathione levels and reverses animal models of glutathione depletion. In two double blind randomised placebo controlled trials, NAC has shown clinical efficacy in both schizophrenia and bipolar disorder. The duration of both of the trials was 6 months, and in both trials participants received 2g daily of NAC or placebo as add-on therapy to treatment as usual. In schizophrenia, (N=140), moderate effect sizes were seen in overall symptomatology, negative symptoms and akathisia. In bipolar disorder, (N=75), outcome measures included measures of mania, depression, global impression, substance use, quality of life, functioning, and tolerability. NAC treated individuals showed a significant benefit on measures of depression, quality of life and functioning at endpoint. Effect sizes were in the moderate to large range. A second RCT examining maintenance effects of NAC in bipolar disorder is nearing completion, as is a trial in unipolar depression. This data implicates oxidative pathways in the pathophysiology of major psychiatric disorders, and supports NAC as a novel adjunctive treatment.