Research on the genetic basis of mental disorders crossed a major watershed this summer. For the first time, specific genes have been discovered that influence susceptibility to schizophrenia, a psychosis that affects nearly 1% of people throughout the world and accounts for about 2.5% of health-care costs (1). In this issue of PNAS, Chumakov and colleagues (2) describe a new human gene, G72, on chromosome 13q34 that interacts with the gene for D-amino acid oxidase (DAAO) on 12q24 to regulate glutaminergic signaling through the N-methyl-D-aspartate (NMDA) receptor pathway. Using traditional positional cloning techniques of linkage and linkage disequilibrium, they show that both of these genes are associated with increased susceptibility to schizophrenia. Therefore, this is the first discovery of a specific gene that also provides a pathogenic molecular mechanism that can account for the major symptoms of a psychiatric disorder. Similarly, two other groups reported this summer that the gene dysbindin on 6p22. 3 (3) and the gene neuregulin 1 on 8p (4) also influence susceptibility to schizophrenia and may operate via the same NMDA mechanism. Each of these gene discoveries came from association analysis targeting chromosomal regions first identified by linkage analysis. The success of groups working on three different chromosomal regions of interest confirms the effectiveness of traditional positional cloning techniques in complex mental disorders. Consequently, these results justify optimism for future progress in unraveling complex disorders in which there is interaction among multiple genetic and environmental variables. However, it is important to recognize both the strengths and the limitations of the genetic and functional strategies used by Chumakov and colleagues (2). It is also important to recognize the continuing significance of the prior work that laid the foundation for these particular experiments.