Tumor suppressor genes are frequently inactivated in cancer by large-scale deletion events or epigenetic silencing, and experimental demonstration of such inactivation has historically been considered as support for assigning tumor suppressive function to a given gene. However, the discovery of a number of chromosomal domains wherein large deletions naturally occur at frequencies up to 100 times the average for the genome as a whole leads us to reevaluate the significance of sporadic deletions found within genes associated with these hotspots. Similarly, our recent demonstration that epigenetic chromatin silencing frequently spreads in cancer cells from gene-poor into gene-rich regions with apparent indifference to the gene content of the affected domain raises questions about the pertinence of inactivation as a criterion for ascribing tumor suppressor function to a given gene. We suggest that a number of putative suppressor genes for which inactivation and/or deletion events have been documented may simply be victims of collateral damage when these events occur, and the implication that these genes are being selected against during cancer progression should in some cases be reassessed. J. Cell. Biochem. 110: 281–287, 2010. © 2010 Wiley-Liss, Inc.