For more than a decade, investigators have been searching for a means of determining the risk of individuals developing cancer by detecting rare oncogenic mutations. The accumulation of mutations and the clonal evolvement of tumors provide opportunities for monitoring disease development and intervening prior to the presentation of clinical symptoms, or determining the risk of disease relapse during remission. A number of techniques, mostly polymerase chain reaction (PCR)-based, have been developed that enable the detection of rare oncogenic mutations within the range of 10(-2) to 10(-4) wild-type cells. Only a handful of procedures enable the detection of intragenic single base mutations at one mutant in 10-6 or better. These ultra-sensitive mutation detection techniques have produced some interesting results regarding single base mutation spectra and frequencies in p53, Harvey-ras, N-ras, and other reporter genes and DNA sequences in human tissues. Although there is evidence that some individuals may harbor cells or clones expressing genomic instability, the connection with the processes of carcinogenesis is still tenuous. There remains a need for rigorous epidemiological studies employing these ultra-sensitive mutation detection procedures. Since genomic instability is considered key to tumor development, the relevance of the detection of hypermutable clones in individuals is discussed in the context of cancer risk.