This review provides a comprehensive overview of clinical and molecular genetic as well as pharmacogenetic studies regarding the clinical phenotype of “psychotic depression.” Results are discussed with regard to the long-standing debate on categorical vs dimensional disease models of affective and psychotic disorders on a continuum from unipolar depression over bipolar disorder and schizoaffective disorder to schizophrenia. Clinical genetic studies suggest a familial aggregation and a considerable heritability (39%) of psychotic depression partly shared with schizoaffective disorder, schizophrenia, and affective disorders. Molecular genetic studies point to potential risk loci of psychotic depression shared with schizoaffective disorder (1q42, 22q11, 19p13), depression, bipolar disorder, and schizophrenia (6p, 8p22, 10p13-12, 10p14, 13q13-14, 13q32, 18p, 22q11-13) and several vulnerability genes possibly contributing to an increased risk of psychotic symptoms in depression (eg, BDNF, DBH, DTNBP1, DRD2, DRD4, GSK-3beta, MAO-A). Pharmacogenetic studies implicate 5-HTT, TPH1, and DTNBP1 gene variation in the mediation of antidepressant treatment response in psychotic depression. Genetic factors are suggested to contribute to the disease risk of psychotic depression in partial overlap with disorders along the affective-psychotic spectrum. Thus, genetic research focusing on psychotic depression might inspire a more dimensional, neurobiologically and symptom-oriented taxonomy of affective and psychotic disorders challenging the dichotomous Kraepelinian view. Additionally, pharmacogenetic studies might aid in the development of a more personalized treatment of psychotic depression with an individually tailored antidepressive/antipsychotic pharmacotherapy according to genotype.