Increasingly, human genes are being identified by the "reverse genetics", or "positional cloning" approach. This molecular genetic strategy is particularly useful in mental illness, for which no readily detectable functional alterations are present to indicate candidate genes. The positional cloning procedure is briefly described. Significant examples of successful positional cloning are presented, including the fragile-X mental retardation syndrome gene. The study of gene expression may be complicated by genetic and non-genetic variability. Genomic imprinting may play a role in several mental illnesses, and may provide an explanation for the unusual inheritance pattern in fragile-X syndrome, for the phenotypic differences observed between Angelman and Prader-Willi syndromes, and for the juvenile onset form of Huntington disease. DNA instability may explain disease anticipation in fragile-X syndrome and myotonic dystrophy. Finally, the prospects of improvements in positional cloning methods for tracking genes responsible for mental illness are briefly discussed.