Epidemiological data pointed to a potential link between cholesterol metabolism and suicide risk. Furthermore, a series of clinical studies in psychiatric patients demonstrated an association between low cholesterol concentrations and increased suicide risk. A meta-analysis of earlier intervention trials showed an association between cholesterol-lowering and increased mortality from suicide, which, however, was not confirmed in recent lipidlowering trials. Although the original assumption needs substantial modification and reconceptualisation, it has sparked new interest in this area of research and stimulated a number of preclinical and clinical studies. In vitro and animal experiments were performed to investigate the modulation of central serotonergic neurotransmission by altering the cholesterol content in neuronal membranes. Based on recently published preliminary data, it was speculated that decreased consumption or depletion of polyunsaturated fatty acids could play a role in the context of depression and suicide. In this article, we review the current evidence for a link between cholesterol, essential fatty acids, depression, and suicide.