Nearly three decades after Robins and Guze's seminal delineation of the steps required to validate a psychiatric diagnosis, a pathophysiologically based classification of psychiatric disorders remains elusive. Contrary to optimistic expectations, approaches to diagnostic validity based on clinical description, laboratory studies, natural history of illness, and familial aggregation have not converged to yield a nosology based on valid disease entities. Defining a rational nosology for disorders of the brain, the body's most complex organ, is clearly one of the great challenges for modern medical science. Nonetheless, fundamental advances in our understanding of the genetic and environmental determinants of disease risk, and of the neural circuitry supporting normal and pathological mental processes promises to form the basis of improved classification in the coming decades. Copyright 2002 S. Karger AG, Basel