Abnormalities of gene dosage are important in human disease. We have developed the differential polymerase chain reaction (PCR) to detect gene amplification and deletion in small amounts of tissues whose DNA may be degraded. The current utility of differential PCR required optimization of DNA isolation procedures, of primer selection approaches, and of PCR conditions. From this experience, we have formulated a theoretical framework for the technique, and describe appropriate applications and potential improvements based on emerging PCR technologies. Special emphasis is placed on the analysis of formalin fixed and paraffin embedded, archived specimens.