The validity of diagnostic definitions in psychiatry is closely tied to the ability to specify their etiology. However, due to the lack of detailed knowledge about causal or susceptibility factors for most psychiatric disorders with a known or suspected familial-genetic origin, current classification systems often fail to achieve this ideal. This paper examines the challenges posed by the criteria for schizophrenia in the International Classification of Diseases, 10th revision (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R), highlighting discrepancies between diagnostic boundaries and phenotype aggregation patterns observed in family studies. The paper emphasizes that clinical diagnoses should be based on distinct etiologies, particularly for psychiatric disorders with a familial-genetic basis. Ideal definitions would be derived from known genetic mutations, but such detailed knowledge is currently lacking for most such disorders. Alternative strategies are needed to define these disorders, and two major criteria for validity are proposed: heritability estimates from twin studies and the strength and specificity of familial aggregation. The paper discusses how these criteria have been used to establish the classification of affective disorders, distinguishing bipolar disorder and unipolar depression. It also explores the impact of familial-genetic studies on the classification of schizoaffective disorders and the validity of diagnostic definitions for schizophrenia and psychotic disorders. Recent studies have shown that negative symptoms are more consistently associated with high familial similarity and genetic loading compared to positive symptoms, yet current classification systems prioritize positive symptoms. The paper concludes that the differences in diagnostic definitions between DSM-III-R, DSM-IV, and ICD-10 have minimal impact on the degree of familial aggregation of schizophrenia. It also highlights that the range of syndromes and durations coaggregating with schizophrenia in families is broader than the diagnostic boundaries proposed by any manual. Linkage studies have failed to reveal a specific relationship between diagnostic categories and susceptibility genes, emphasizing the limited value of current diagnostic definitions for identifying specific genetic vulnerabilities.The validity of diagnostic definitions in psychiatry is closely tied to the ability to specify their etiology. However, due to the lack of detailed knowledge about causal or susceptibility factors for most psychiatric disorders with a known or suspected familial-genetic origin, current classification systems often fail to achieve this ideal. This paper examines the challenges posed by the criteria for schizophrenia in the International Classification of Diseases, 10th revision (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R), highlighting discrepancies between diagnostic boundaries and phenotype aggregation patterns observed in family studies. The paper emphasizes that clinical diagnoses should be based on distinct etiologies, particularly for psychiatric disorders with a familial-genetic basis. Ideal definitions would be derived from known genetic mutations, but such detailed knowledge is currently lacking for most such disorders. Alternative strategies are needed to define these disorders, and two major criteria for validity are proposed: heritability estimates from twin studies and the strength and specificity of familial aggregation. The paper discusses how these criteria have been used to establish the classification of affective disorders, distinguishing bipolar disorder and unipolar depression. It also explores the impact of familial-genetic studies on the classification of schizoaffective disorders and the validity of diagnostic definitions for schizophrenia and psychotic disorders. Recent studies have shown that negative symptoms are more consistently associated with high familial similarity and genetic loading compared to positive symptoms, yet current classification systems prioritize positive symptoms. The paper concludes that the differences in diagnostic definitions between DSM-III-R, DSM-IV, and ICD-10 have minimal impact on the degree of familial aggregation of schizophrenia. It also highlights that the range of syndromes and durations coaggregating with schizophrenia in families is broader than the diagnostic boundaries proposed by any manual. Linkage studies have failed to reveal a specific relationship between diagnostic categories and susceptibility genes, emphasizing the limited value of current diagnostic definitions for identifying specific genetic vulnerabilities.