Emil Kraepelin introduced clinical and scientific methodology into psychiatry research and thus helped firmly establish psychiatry into medicine. There have been varying, good and bad times for people with mental illness and psychiatry since Kraepelin’s death. But the legacy of his textbook and research agenda has continued to be of central importance to psychiatry to the present day, and however underfunded, psychiatry has been pursuing state-of-the-art research on mental health and mental illness with a good visibility. Psychiatric research needs to focus on a better understanding of the aetiopathology of mental disorders, to develop (bio)-markers that characterise pathophysiologically distinct subgroups and to implement mechanistically informed treatments. This will be crucial to make precision psychiatry a clinical reality. To make significant progress, there is a need to address relevant pathophysiological questions as well as a need to form teams of research specialists dedicated to answering these pressing questions. Once diagnostic and treatment targets are identified, clinical studies from single-case studies to large-scale implementation randomised controlled trials (RCTs) can bring these targets from the laboratory to the clinic. The final goal is to develop innovative personalised treatment strategies with a particular focus on conditions that are currently treatment-resistant. These include cognitive impairments and the so-called negative symptoms including anhedonia, avolition and lack of drive. There is no need for a pessimistic assessment of the progress achieved in the last 100 years; however, excellent research, as well as serendipity, is required to ensure transformative innovations. Both positive and negative findings need to be published and sufficient funding secured.