A few hundred disease genes have been cloned and analysed since the advent of recombinant DNA technology made this possible fifteen years ago. The vast majority of these genes have been identified because there was pre-existing knowledge about the basic biochemical defect. In many instances, this reflected purification of the normal protein product and partial amino acid sequence determination; in other cases antibodies against the protein product were utilized. In a few cases (such as transforming oncogenes) the function of the gene was directly used to clone it. While these strategies, referred to here as" functional cloning", have been remarkably successful, they are limited to disorders for which biological information about the basic genetic defect exists. Unfortunately, for the vast majority of single gene disorders listed in McKusick's catalog,