The genome is traditionally treated as a Turing tape or Read-Only Memory (ROM) subject to change by copying errors. This default assumption of accidental mutation arose from the inevitable ignorance of the mechanisms of genome change in the 19th and early 20th Centuries. It contributed to the historical divorce between physiology, homeostasis and regulation, on the one hand, and studies of genetics and evolution, on the other. In contrast to early assumptions about genomic accidents, research dating back to the 1930s has shown that genetic change is the result of cell-mediated processes, not simply damage to the DNA. McClintock’s study of X-ray mutagenesis found that this mode of induced genome change arose because ionizing radiation caused chromosome breakage and cells have the capacity to detect, mobilize and join broken ends together, generating chromosome rearrangements (McClintock 1984; McClintock 1987). In other words, X-ray mutagenesis resulted from a physiological response to genome damage. This cell-active view of genome change applies to all scales of variation, from point mutations to large-scale genome rearrangements and whole genome duplications (WGDs) (Shapiro 2011). As with X-rays, we now recognize all mutagen-induced change to result from the action of error-prone repair processes. The smallest “point mutations” involve the action of so-called “trans-lesion mutator polymerases” (Napolitano, Janel-Bintz et al. 2000; Goodman 2002). Larger chromosome changes involve biochemical repair of double-strand breaks by “non-homologous end-joining” (NHEJ) complexes (Lieber, Gu et al. 2010) or the action of mobile genetic elements (Kazazian 2004; Nakayashiki 2011). Many large changes, including whole genome duplication (WGD), occur because of epigenetic modifications in response to stress conditions, chemical stimuli, or breeding between different species (http://shapiro.bsd.uchicago.edu/ExtraRefs.CellularRegulationNaturalGeneticEngineering.shtml, http://shapiro.bsd.uchicago.edu/ExtraRefs.WholeGenomeDoublingCriticalStagesEvolution.shtml, http://shapiro.bsd.uchicago.edu/TableII.7.shtml, http://shapiro.bsd.uchicago.edu/TableII.8.shtml, and http://shapiro.bsd.uchicago.edu/TableII.10.shtml). Moreover, cell-mediated changes to the genome can be targeted to particular locations in the genome by well-established molecular mechanisms (http://shapiro.bsd.uchicago.edu/TableII.11.shtml). It is possible, therefore, to begin understanding the genome evolutionary process as a sophisticated physiological response to ecological modifications and disruptions. The take-home lesson of this lecture is that DNA changes are biological (biochemical, physiological) and not accidental in origin. Consequently, it is necessary to revise our concept of genome storage to accommodate the potentials of a Read-Write (RW) storage system. The evolutionary implications of this conceptual change are profound. Cell inscriptions on the genome, like all biochemical and physiological activities, are subject to regulation by control circuitry, in particular epigenetic controls. The interactions between these control circuits and the environment make it possible to begin a detailed experimental investigation of the relation between ecological and genomic changes in evolution.