Most human tumors and tumor cell lines exhibit numerical and structural chromosomal abnormalities. The goal of this study was to determine the ongoing rates of structural and numerical instability in selected cancer cell lines and to investigate the consequences of these rates to karyotypic progression. We studied two colorectal (HCT-116 and HT-29) and two ovarian (SKOV-3 and OVCAR-8) cancer cell lines and their single cell subclones. We found that the signature karyotypes of all four cell lines were distinct and each aberrant. Whereas high rates of ongoing structural and/ or numerical chromosomal instability could be demonstrated in all cell lines, there was a relative stability of the consensus karyotype over many generations. No new clonal structural chromosomal reconfigurations emerged and the few numerical changes of karyotypes were restricted to abnormal chromosomes. This implies a kind of genomic optimization under the conditions of cell culture and suggests a link between genomic stabilization and cell propagation. We have been able to support this possibility by computer modeling. We did not observe a profound difference in the rates of numerical or structural instability in the cell lines with a replication error phenotype (RER+) versus the other cell lines.