Cancer cells proliferate and metastasize against the body's defense mechanisms due to their ability to change in response to challenges, both from the body's internal defenses as well as those from external sources, such as radiation and chemotherapy. This ability of tumor cell populations to change and grow in response to these stresses as well as to hold populations of cells with diverse abilities has been termed 'tumor cell heterogeneity'. Tumor cell heterogeneity is thought to arise in cancer cell populations as a result of genetic instability, an undefined process by which the genetic material of the cell is rendered more labile and more likely to undergo changes in structure, conformation, and function. DNA is structurally and functionally organized by the nuclear matrix, the dynamic RNA-protein skeleton of the nucleus. We provide here a proposal that provides a framework for understanding genetic instability in terms of an unstable nuclear matrix.