When no endopathological abnormalities are available to serve as classifying criteria, symptom clusters are generally used as substitutes. They then form the core of particular functional diseases, especially in psychiatry. The selection of symptom clusters on the basis of clinical impression is the predominant procedure, but it is subjective and arbitrary. To remedy this shortcoming, cluster-searching methods of a sophisticated statistical nature have been introduced, though they have not so far been conspicuously successful. In some functional psychiatric diseases, such as phobic neurosis, depressive neurosis, war neurosis, and compensation neurosis, exopathological environmental, but normal, events form the classifying criteria. They are presumed to activate idiosyncratic endopathological predispositions. The classification of organic diseases relies on endopathological and inherited exopathological abnormalities as classifying criteria. As an illustration of the establishment of an inherited exopathological disease, the discovery of phenylketonuria as a clinical sign and the gradual elucidation of its pathogenesis are described.