Spontaneous mutations in somatic cells may engender several pathologic processes, including cancer. The sources of these mutations remain to be established. We present a conceptual framework in which to analyze the sources of spontaneous mutations and focus here on 3 endogenous processes that have the potential to generate spontaneous sequence alterations in DNA. These are: replication errors, depurination of DNA, and damage to DNA by the generation of active-oxygen species. Each of these processes occurs more frequently than the rate of mutagenesis in somatic cells, but are repaired by different and overlapping mechanisms. Model systems are being developed to determine the spectrum of mutations produced by each of these processes in vitro. A comparison of these spectra with the overall spectrum of spontaneous mutations in somatic cells may help to determine the contribution of each of these processes to spontaneous mutation.