Over the past century, the definition and classification of psychiatric disorders has evolved through a combination of historical trends, clinical observations, and empirical research. The current nosology, instantiated in the DSM-5 and ICD-10, rests on descriptive criteria agreed upon by a consensus of experts. While the development of explicit criteria has enhanced the reliability of diagnosis, the validity of the current diagnostic categories has been the subject of debate and controversy. Genetic studies have long been regarded as a key resource for validating the boundaries among diagnostic categories. Genetic epidemiologic studies have documented the familiality and heritability of clinically defined psychiatric disorders and molecular genetic studies have begun to identify specific susceptibility variants. At the same time, there is growing evidence from family, twin and genomic studies that genetic influences on psychiatric disorders transcend clinical boundaries. Here I review this evidence for cross-disorder genetic effects and discuss the implications of these findings for psychiatric nosology. Psychiatric genetic research can inform a bottom-up reappraisal of psychopathology that may help the field move beyond a purely descriptive classification and toward an etiology-based nosology.