The main objective of this review was to evaluate studies on the diagnosis, treatment, and course of schizotypal personality disorder and to provide a clinical guidance on the basis of that evaluation. A systematic search in the PubMed/MEDLINE databases was conducted. Two independent reviewers extracted and assessed the quality of the data. A total of 54 studies were eligible for inclusion: 18 were on diagnostic instruments; 22, on pharmacological treatment; 3, on psychotherapy; and 13, on the longitudinal course of the disease. We identified several suitable and reliable questionnaires for screening (PDQ-4+ and SPQ) and diagnosing (SIDP, SIDP-R, and SCID-II) schizotypal personality disorder. Second-generation antipsychotics (mainly risperidone) were the most often studied drug class and were described as beneficial. Studies on the longitudinal course described a moderate remission rate and possible conversion rates to other schizophrenia spectrum disorders. Because of the heterogeneity of the studies and the small sample sizes, it is not yet possible to make evidence-based recommendations for treatment. This is a systematic evaluation of diagnostic instruments and treatment studies in schizotypal personality disorder. We conclude that there is currently only limited evidence on which to base treatment decisions in this disorder. Larger interventional trials are needed to provide the data for evidence-based recommendations.