The search for biomarkers to aid in the diagnosis and prognosis of psychiatric conditions and predict response to treatment is a focus of twenty-first century medicine. The current lack of biomarkers in routine use is attributable in part to the existing way mental health conditions are diagnosed, being based upon descriptions of symptoms rather than causal biological evidence. New ways of conceptualizing mental health disorders together with the enormous advances in genetic, epidemiological, and neuroscience research are informing the brain circuits and physiological mechanisms underpinning behavioural constructs that cut across current diagnostic DSM-5 categories. Combining these advances with ‘Big Data’, analytical approaches offer new opportunities for biomarker development. Here we provide an introductory perspective to this volume, highlighting methodological strategies for biomarker identification; ranging from stem cells, immune mechanisms, genomics, imaging, network science to cognition. Thereafter we emphasize key points made by contributors on affective disorders, psychosis, schizophrenia, and autism spectrum disorder. An underlying theme is how preclinical and clinical research are informing biomarker development and the importance of forward and reverse translation approaches. In considering the exploitation of biomarkers we note that there is a timely opportunity to improve clinical trial design informed by patient ‘biological’ and ‘psychological’ phenotype. This has the potential to reinvigorate drug development and clinical trials in psychiatry. In conclusion, we are poised to move from the descriptive and discovery phase to one where biomarker panels can be evaluated in real-life cohorts. This will necessitate resources for large-scale collaborative efforts worldwide. Ultimately this will lead to new interventions and personalized medicines and transform our ability to prevent illness onset and treat complex psychiatric disorders more effectively.