Objective: Relative to recent successes in elucidating the genetic mechanisms associated with complex diseases, including macular degeneration, diabetes mellitus, type 2, heart disease, and cancer, molecular genetic approaches to psychiatric illness have met with more limited success. While factors such as small allelic effects, allelic heterogeneity, and variation in population substructure have received considerable attention in attempt to explain the paucity of significant results in psychiatric genetics, significantly less focus has been directed toward phenotypic factors. Method: Data derived from molecular genetic studies of the psychosis phenotype in patients with a range of psychiatric illnesses are reviewed. Results: Available data suggest that genes do not respect the boundaries of the current diagnostic system but may confer risk for symptom-based phenotypic variation that traverses those boundaries. Conclusions: Molecular genetic studies offer convincing evidence for a relation between genetic variation and symptom-based phenotypic variation within psychiatric illness. These data may provide novel insights into the pathophysiology of schizophrenia and other related disorders. The exploration of relations between genetic variation and symptom variation that traverses traditional diagnostic boundaries may ultimately lead to more refined classification systems that more closely reflect the genetic etiology of psychiatric illness.