Two decades of research on the origin, course and treatment of mental illness based on the traditional diagnostic framework of the DSM have revealed the artificial nature of this system and showed its constraints on further progress. It has become clear that psychiatry in the 21st century has to transcend symptomatic categories and establish much more fine-grained, neurobiological mechanism informed classification and treatment strategies of mental illness as brain disorders. This is contrasted by numerous promising developments in genomics, neuroscience and experimental clinical research. Schizophrenia, Bipolar Disorder and Major Depression have a broad shared biological basis and previous studies have identified numerous genetic and environmental risk factors. Integrative genomic analyses have shown that genetic risk predominantly impacts a relatively small number of pathways and neurobiological systems, including the immune system, neuroplasticity and neurotransmission as well as metabolism and oxidative stress regulation, in part mediated by environmental and life history risk factors. Moreover, multiple genetic studies have highlighted an association of polygenic risk with treatment response, indicating multiple biological traits influence treatment response. Although Psychiatry is lacking behind other fields of Medicine in genomic discovery and translation, the presentation will illustrate some avenues of how a multi-omics research strategy can enhance discovery of biological systems and pathways relevant to mental disorders. To that end, the presented evidence suggests how genomics could be closely interacting with other research strategies (e.g. experimental, imaging, pharmacology, clinical trial, bioinformatics, big data, epidemiology, hospitals) to facilitate translation within a framework of Systems Medicine in Psychiatry.