To quote Drake et al (1983), "The list of mutagenic mechanisms is long, and it is far more difficult to write the encyclopedia of all possible errors than the few chapters of correct procedures". We are just beginning to appreciate the "correct procedures" for replication and repair, and these require more than a "few chapters" to describe (for two excellent recent texts, see Friedberg et al, 1995 and DePamphilis, in press). Here we have considered several of the key steps and principles for high fidelity DNA synthesis and how these may be perturbed to destabilize the genome. Within this rich intellectual framework, we can anticipate the discovery of new cancer causing genes in the near future, especially given the flurry of activity resulting from recent progress on the relationships between cancer and defective mismatch and excision repair processes.