Background <p>Prader–Willi syndrome (PWS) is highly associated with psychiatric comorbidity.</p> Objectives <p>This article investigates the prevalence of mental disorders in PWS, explores their association with neurobiological foundations, and outlines the resulting clinical recommendations.</p> Methods <p>An evaluation of the scientific literature in the context of clinical experience from the special outpatient clinic for mental health in rare syndromic disorders at Hannover Medical School.</p> Results <p>Psychiatric manifestations are present in 44–89% of PWS patients, with disruptive behavior, skin picking, psychosis, compulsive symptoms, and affective disorders being the most common. PWS psychosis differs from schizophrenic psychosis and can be difficult to treat in some cases. Treatment approaches exist for disruptive behavior, affective symptoms, and compulsive symptoms.</p> Conclusions <p>Knowledge of the neurobiological basis of PWS is necessary for the adequate treatment of psychiatric disorders. In addition to pharmacological therapies, behavioral interventions and environmental control should also be included.</p>