Chromosomal instability is a common feature of human tumors, including oral cancer. Although a tumor karyotype may remain quite stable over time, chromosomal instability can lead to 'variations on a theme' of a clonal cell population, often with each cell within a tumor possessing a different karyotype. Thus, chromosomal instability appears to be an important acquired feature of tumor cells, since propagation of such a diverse cell population may facilitate evasion of standard therapies. There are several sources of chromosomal instability, although the primary causes appear to be defects in chromosomal segregation, telomere stability, cell-cycle checkpoint regulation, and the repair of DNA damage. Our understanding of the biological basis of chromosomal instability in cancer cells is increasing rapidly, and we are finding that the seemingly unrelated origins of this phenomenon may actually be related through the complex network of cellular signaling pathways. Here, we review the general causes of chromosomal instability in human tumors. Specifically, we address the state of our knowledge regarding chromosomal instability in oral cancer, and discuss various mechanisms that enhance the ability of cancer cells within a tumor to express heterogeneous karyotypes. In addition, we discuss the clinical relevance of factors associated with chromosomal instability as they relate to tumor prognosis and therapy.